Abstract:

There is provided compounds of formula (I), wherein R1, R2,
R3, R4, R41 to R46, A, B and G have meanings given in
the description, which are useful in the prophylaxis and in the treatment
of arrhythmias, in particular atrial and ventricular arrhythmias.

54. A compound according to claim 53 which is
(2-{7-[3-(4-cyanophenoxy)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}et-
hyl) carbamic acid tert-butyl ester.

55. A compound according to claim 53 which is
(3-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}pro-
pyl) carbamic acid tert-butyl ester.

56. A compound according to claim 53 which is
7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid
tert-butyl ester.

57. A compound according to claim 53 which is
(2-{7-[2-(4-cyano-2-fluoro-phenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]no-
n-3-yl}ethyl) carbamic acid tert-butyl ester.

58. A compound according to claim 53 which is
(3-{7-[2-(4-cyano-2-fluoro-phenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]no-
n-3-yl}propyl) carbamic acid tert-butyl ester.

Description:

FIELD OF THE INVENTION

[0001]This invention relates to novel pharmaceutically useful compounds,
in particular compounds which are useful in the treatment of cardiac
arrhythmias.

BACKGROUND AND PRIOR ART

[0002]Cardiac arrhythmias may be defined as abnormalities in the rate,
regularity, or site of origin of the cardiac impulse or as disturbances
in conduction which causes an abnormal sequence of activation.
Arrhythnias may be classified clinically by means of the presumed site of
origin (i.e. as supraventricular, including atrial and atrioventricular,
arrhythmias and ventricular arrhythmias) and/or by means of rate (i.e.
bradyarrhythmias (slow) and tachyarrhythmias (fast)).

[0003]In the treatment of cardiac arrhythmias, the negative outcome in
clinical trials (see, for example, the outcome of the Cardiac Arrhythmia
Suppression Trial (CAST) reported in New England Journal of Medicine,
321, 406 (1989)) with "traditional" antiarrhythmic drugs, which act
primarily by slowing the conduction velocity (class I antiarrhythmic
drugs), has prompted drug development towards compounds which selectively
delay cardiac repolarization, thus prolonging the QT interval. Class III
antiarrhythmic drugs may be defined as drugs which prolong the
trans-membrane action potential duration (which can be caused by a block
of outward K+ currents or from an increase of inward ion currents)
and refractoriness, without affecting cardiac conduction.

[0004]One of the key disadvantages of hitherto known drugs which act by
delaying repolarization (class III or otherwise) is that they all are
known to exhibit a unique form of proarrhythmia known as torsades de
pointes (turning of points), which may, on occasion be fatal. From the
point of view of safety, the minimisation of this phenomenon (which has
also been shown to be exhibited as a result of administration of
non-cardiac drugs such as phenothiazines, tricyclic antidepressants,
antihistamines and antibiotics) is a key problem to be solved in the
provision of effective antiarrhythmic drugs.

[0006]Certain oxabispidine compounds are disclosed as chemical curiosities
in Chem. Ber., 96, 2872 (1963). The use of certain other oxabispidine
compounds in the treatment of cardiac arrhythmias is disclosed in WO
01/28992. Methods for the preparation of such oxabispidine compounds are
disclosed in WO 02/28863, WO 02/28864, WO 02/83690 and WO 02/83691.
Oxabispidine compounds in which one or both of the N-atoms bears a
substituent that includes an "in-chain" sulfonamide group are neither
disclosed nor suggested.

[0007]We have surprisingly found that a novel group of oxabispidine-based
compounds exhibit electrophysiological activity and are therefore
expected to be useful in the treatment of cardiac arrhythmias. The novel
group of oxabispidine-based compounds has advantageous properties
compared to compounds of the prior art, such as enhanced potency,
enhanced selectivity, and/or reduction of total clearance. These
advantageous properties can distinguish the use of such compounds as
pharmaceutical agents by lowering the daily clinical dose, lengthening
the duration of action, and/or improving the side effect profile.

DISCLOSURE OF THE INVENTION

[0008]According to the invention there is provided compounds of formula I,

[0010]R5a represents H or C1-6 alkyl (which latter group is
optionally substituted by one or more substituents selected from --OH,
halo, cyano, nitro, --S(O)2N(R9b)R9c and
--N(R9b)S(O)2R9d);

[0011]R5b to R5e independently represent, at each occurrence
when used herein, H, C1-6 alkyl (which latter group is optionally
substituted by one or more substituents selected from --OH, halo, cyano,
nitro, aryl, Het2, --S(O)2N(R9b)R9c and
--N(R9b)S(O)2R9d), aryl or Het3, or R5d or
R5e, together with, respectively, R8a or R8b, may
represent C3-6 alkylene (which alkylene group is optionally
interrupted by an O atom and/or is optionally substituted by one or more
C1-3 alkyl groups);

[0014]R7 represents, at each occurrence when used herein, C1-12
alkyl (optionally substituted by one or more substituents selected from
--OH, halo, cyano, nitro, aryl, C1-6 alkoxy, Het4,
--S(O)2N(R9b)R9c and --N(R9b)S(O)2R9d);

[0016]R11a to R11d independently represent H, C1-6 alkyl
(optionally substituted by one or more substituents selected from --OH,
halo, cyano, nitro and aryl), aryl, or R11c and R11d together
represent C3-6 alkylene;

[0017]R12a and R12b independently represent C1-6 alkyl
(optionally substituted by one or more substituents selected from --OH,
halo, cyano, nitro and aryl) or aryl;

[0018]D represents, at each occurrence when used herein, a direct bond or
C1-6 alkylene;

[0019]X represents O or S;

[0020]R9a represents, at each occurrence when used herein, C1-6
alkyl (optionally substituted by one or more substituents selected from
--OH, halo, cyano, nitro, aryl, --S(O)2N(R9b)R9c and
--N(R9b)S(O)2R9d) or aryl;

[0021]R9b represents, at each occurrence when used herein, H or
C1-6 alkyl;

[0022]R9c and R9d independently represent, at each occurrence
when used herein, C1-6 alkyl (optionally substituted by one or more
substituents selected from --OH, halo, cyano, nitro, aryl and Het6),
aryl or Het7, or R9c represents H;

[0028]R16a to R16d independently represent, at each occurrence
when used herein, C1-6 alkyl (optionally substituted by one or more
substituents selected from halo, aryl and Het10), aryl, Het11,
or R16a and R16d independently represent H;

[0029]R17a and R17b independently represent, at each occurrence
when used herein, H or C1-6 alkyl (optionally substituted by one or
more substituents selected from halo, aryl and Het12), aryl,
Het13, or together represent C3-6 alkylene, optionally
interrupted by an O atom;

[0030]E represents, at each occurrence when used herein, a direct bond or
C1-4 alkylene;

[0035]B represents -Z-{[C(O)]aC(H)(R20a)}b--,
-Z-[C(O)]cN(R20b)--, -Z-N(R20c)S(O)2--,
-Z-S(O)2N(R20d)--, -Z-S(O)n--, -Z-O-- (in which latter six
groups, Z is attached to the carbon atom bearing R2 and R3),
--N(R20e)-Z-, --N(R20f)S(O)2-Z-,
--S(O)2N(R20g)-Z-- or --N(R20h)C(O)O-Z- (in which latter
four groups, Z is attached to the phenyl or pyridyl group that is
optionally substituted by R4);

[0036]J represents C1-6 alkylene optionally interrupted by
--S(O)2N(R19d)-- or --N(R19e)S(O)2-- and/or
optionally substituted by one or more substituents selected from --OH,
halo and amino;

[0040]R19a to R19e independently represent, at each occurrence
when used herein, H or C1-6 alkyl;

[0041]R20a represents H or, together with a single R4
substituent at a position on the phenyl or pyridyl group that is ortho-
to the position at which the group B is attached, R20a represents
C2-4 alkylene optionally interrupted or terminated by O, S, N(H) or
N(C1-6 alkyl);

[0042]R20b represents H, C1-6 alkyl or, together with a single
R4 substituent at a position on the phenyl or pyridyl group that is
ortho- to the position at which the group B is attached, R20b
represents C2-4 alkylene;

[0043]R20c to R20j independently represent, at each occurrence
when used herein, H or C1-6 alkyl;

[0044]G represents CH or N;

[0045]R4 represents one or more optional substituents selected from
--OH, cyano, halo, nitro, C1-6 alkyl (optionally terminated by
--N(H)C(O)OR21a), C1-6 alkoxy, --N(R22a)R22b,
--C(O)R22c, --C(O)OR22d, --C(O)N(R22e)R22f,
--N(R22g)C(O)R22h, --N(R22i)C(O)N(R22i)R22k,
--N(R22m)S(O)2R21b, --S(O)2N(R22n)R22o,
--S(O)2R21c, --OS(O)2R21d and aryl and an R4
substituent in a position on the phenyl or pyridyl group that is ortho-
to the position at which the group B is attached may [0046](i) together
with R20a, represent C2-4 alkylene optionally interrupted or
terminated by O, S or N(H) or N(C1-6 alkyl), or [0047](ii) together
with R20b, represent C2-4 alkylene;

wherein each aryl and aryloxy group, unless otherwise specified, is
optionally substituted;provided that

[0051](a) at least one of the following is the case [0052](i) R1
represents C1-12 alkyl (which alkyl group is substituted by one or
more groups including at least one --S(O)2N(R9b)R9c and/or
N(R9b)S(O)2R9d group), [0053](ii) A represents
-J-S(O)2N(R9b)-- or -J-N(R19c)S(O)2--, [0054](iii) J
is interrupted by --S(O)2N(R19d)-- or
--N(R19e)S(O)2--, [0055](iv) B represents
-Z-N(R20c)S(O)2--, -Z-S(O)2N(R20d)--,
--N(R20f)S(O)2-Z- or --S(O)2N(R20g)-Z- and/or
[0056](v) Z is interrupted by --N(R20i)S(O)2-- or
--S(O)2N(R20j)--;

[0057](b) when A represents -J-N(R19a)--, -J-N(R19c)S(O)2--
or -J-O--, then: [0058](i) J does not represent C1 alkylene or
1,1-C2-6 alkylene; and [0059](ii) B does not represent
--N(R20b)--, --N(R20c)S(O)2--, --S(O)n--, --O--,
--N(R20f)S(O)2-Z- or --N(R20h)C(O)O-Z when R2 and
R3 do not together represent ═O; and

[0060](c) when R2 represents --OR3 or --N(R14)(R15),
then: [0061](i) A does not represent -J-N(R19a)--,
-J-N(R19c)S(O)2-- or -J-O--; and [0062](ii) B does not
represent --N(R20b)--, --N(R20c)S(O)2--, --S(O)n--,
--O--, --N(R20f)S(O)2-Z- or --N(R20h)C(O)O-Z-;or a
pharmaceutically acceptable derivative thereof.

[0063]For the avoidance of doubt it is to be understood that where in this
specification a group is qualified by `hereinbefore defined`, `defined
hereinbefore` or `defined above` the said group encompasses the first
occurring and broadest definition as well as each and all of the
particular definitions for that group.

[0064]Unless otherwise specified, alkyl groups and alkoxy groups as
defined herein may be straight-chain or, when there is a sufficient
number (i.e. a minimum of three) of carbon atoms be branched-chain,
and/or cyclic. Further, when there is a sufficient number (i.e. a minimum
of four) of carbon atoms, such alkyl and alkoxy groups may also be part
cyclic/acyclic. Such alkyl and alkoxy groups may also be saturated or,
when there is a sufficient number (i.e. a minimum of two) of carbon
atoms, be unsaturated and/or interrupted by one or more oxygen and/or
sulfur atoms. Unless otherwise specified, alkyl and alkoxy groups may
also be substituted by one or more halo, and especially fluoro, atoms.

[0065]Unless otherwise specified, alkylene groups as defined herein may be
straight-chain or, when there is a sufficient number (i.e. a minimum of
two) of carbon atoms, be branched-chain. Such alkylene chains may also be
saturated or, when there is a sufficient number (i.e. a minimum of two)
of carbon atoms, be unsaturated and/or interrupted by one or more oxygen
and/or sulfur atoms. Unless otherwise specified, alkylene groups may also
be substituted by one or more halo atoms.

[0066]The term "aryl", when used herein, includes C6-10 aryl groups
such as phenyl, naphthyl and the like. The term "aryloxy", when used
herein includes C6-10 aryloxy groups such as phenoxy, naphthoxy and
the like. For the avoidance of doubt, aryloxy groups referred to herein
are attached to the rest of the molecule via the O-atom of the oxy-group.
Unless otherwise specified, aryl and aryloxy groups may be substituted by
one or more substituents including --OH, halo, cyano, nitro, C1-6
alkyl, C1-6 alkoxy, --N(R22a)R22b, --C(O)R22c,
--C(O)OR22d, --C(O)N(R2e)R22f,
--N(R22g)C(O)R22h, --N(R22m)S(O)2R21b,
--S(O)2N(R22n)R22o, --S(O)2R21c, and/or
OS(O)2R21d (wherein R21b to R21d and R22a to
R22o are as hereinbefore defined). When substituted, aryl and
aryloxy groups are preferably substituted by between one and three
substituents.

[0067]The term "halo", when used herein, includes fluoro, chloro, bromo
and iodo.

[0069]Values of Het1 that may be mentioned include
2,3-dihydrobenzo[b]furanyl, furanyl, imidazolyl, isoxazolyl, pyridinyl
and thiazolyl.

[0070]Values of Het7 that may be mentioned include imidazolyl and
isoxazolyl.

[0071]Substituents on Het (Het1, Het2, Het3, Het4,
Het5, Het6, Het7, Het8, Het9, Het10,
Het11, Het12 and Het13) groups may, where appropriate, be
located on any atom in the ring system including a heteroatom. The point
of attachment of Het (Het1, Het2, Het3, Het4,
Het5, Het6, Het7, Het8, Het9, Het10,
Het11, Het12 and Het13) groups may be via any atom in the
ring system including (where appropriate) a heteroatom, or an atom on any
fused carbocyclic ring that may be present as part of the ring system.
Het (Het1, Het2, Het3, Het4, Het5, Het6,
Het7, Het8, Het9, Het10, Het11, Het12 and
Het13) groups may also be in the N- or S-oxidised form.

[0072]Pharmaceutically acceptable derivatives include salts and solvates.
Salts which may be mentioned include acid addition salts.

[0076]The compounds of the invention may exhibit tautomerism. All
tautomeric forms and mixtures thereof are included within the scope of
the invention.

[0077]The compounds of the invention may also contain one or more
asymmetric carbon atoms and may therefore exhibit optical and/or
diastereoisomerism. Diastereoisomers may be separated using conventional
techniques, e.g. chromatography or fractional crystallisation. The
various stereoisomers may be isolated by separation of a racemic or other
mixture of the compounds using conventional, e.g. fractional
crystallisation or HPLC, techniques. Alternatively the desired optical
isomers may be made by reaction of the appropriate optically active
starting materials under conditions which will not cause racemisation or
epimerisation, or by derivatisation, for example with a homochiral acid
followed by separation of the diastereomeric esters by conventional means
(e.g. HPLC, chromatography over silica). All stereoisomers are included
within the scope of the invention.

[0078]Abbreviations are listed at the end of this specification.

[0079]Preferred values of each variable group are as follows. Such values
may be used where appropriate with any of the values, definitions,
claims, aspects or embodiments defined hereinbefore or hereinafter. In
particular, each may be used as an individual limitation on the broadest
definition of formula (I). Preferred compounds of the invention include
those in which:

[0080]R1 represents C1-8 alkyl (which alkyl group is optionally
substituted by one or more groups selected from halo, aryl (which latter
group is optionally substituted by one or more substituents selected from
--OH, halo, cyano, nitro, C1-4 alkyl, C1-4 alkoxy (which latter
two groups are optionally substituted by one or more halo atoms),
--C(O)R22c and --S(O)2R21c), Het , N(R5a)R6,
--C(O)R5b, --OR5c, --C(O)N(R8a)R5d,
OC(O)N(R8b)R5e, --S(O)2R9a,
--S(O)2N(R9b)R9c and --N(H)S(O)2R9d) or R1
represents --C(O)OR7, --C(O)N(R8a)R5d or
--S(O)2R9a;

[0081]R5a represents H or C1-5 alkyl;

[0082]R5b to R5e independently represent, at each occurrence
when used herein, H, C1-6 alkyl (which latter group is optionally
substituted by one or more substituents selected from cyano, nitro and
optionally substituted aryl), aryl (which latter group is optionally
substituted by one or more substituents selected from --OH, halo, cyano,
nitro, N(R22a)R22b (in which latter group R22a and
R22b together represent C3-6 alkylene), C1-5 alkyl and
C1-5 alkoxy (which latter two groups are optionally substituted by
one or more halo atoms)), Het3, or R5d, together with R8a,
represents C4-5 alkylene (which alkylene group is optionally
interrupted by an O atom); R6 represents H, C1-6 alkyl,
optionally substituted aryl --C(O)R10a, --C(O)OR10b or
--C(O)N(H)R10c;

[0083]R10a and R10b independently represent C1-5 alkyl
(optionally substituted by one or more substituents selected from halo
and optionally substituted aryl) or optionally substituted aryl;

[0088]D represents, at each occurrence when used herein, a direct bond or
C1-4 alkylene;

[0089]R9a represents C1-6 alkyl (optionally substituted by one
or more halo groups) or optionally substituted aryl;

[0090]R9b represents H or C1-3 alkyl;

[0091]R9c and R9d independently represent, at each occurrence
when used herein, C1-5 alkyl (optionally substituted by one or more
substituents selected from halo, optionally substituted aryl and
Het6), optionally substituted aryl or Het7, or R9c
represents H;

[0101]A represents C1-4 alkylene optionally substituted by one or
more substituents selected from OH and amino, --C1-3
n-alkylene-S(O)2N(H)-- or --C2-3 n-alkylene-N(H)S(O)2--
(in which latter two groups, alkylene is attached to the oxabispidine
ring nitrogen);

[0104]R20b represents H, C1-4 alkyl or, together with a single
R4 substituent at a position on the phenyl or pyridyl group that is
ortho- to the position at which the group B is attached, R20b
represents C2-4 alkylene;

[0105]R20c and R20d independently represent H or C1-3
alkyl;

when G represents N, G is in the ortho- or, in particular, the
para-position relative to the point of attachment of B;when G represents
N, R4 is absent (i.e. represents H) or represents a single cyano
group;

[0106]R4 represents one or more substituents selected from --OH,
cyano, halo, nitro, C1-6 alkyl, C1-6 alkoxy,
--C(O)N(R22e)R22f, and N(R22m)S(O)2--C1-4 alkyl,
or an R4 substituent in a position on the phenyl or pyridyl group
that is ortho- to the position at which the group B is attached may,
together with R20b, represent C2-4 alkylene;

optional substituents on aryl and aryloxy groups are, unless otherwise
stated, one or more substituents selected from halo, cyano, nitro,
C1-4 alkyl, C1-4 alkoxy (which latter two groups are optionally
substituted by one or more halo atoms), --N(H)S(O)2R21b and
--S(O)2N(H)R22o.

[0110]More preferred compounds of the invention include those in which:

[0111]R1 represents straight- or branched-chain or part
cyclic/acyclic C1-6 alkyl, which alkyl group is optionally
interrupted by oxygen and/or substituted by: (i) one or more halo or
OR5c groups; and/or (ii) one group selected phenyl (which latter
group is optionally substituted by one or more (e.g. one to three)
substituents selected from halo, cyano, C1-3 alkyl, C1-3 alkoxy
(which latter two groups are optionally substituted by one or more halo
(e.g. fluoro) atoms), --C(O)--C1-3 alkyl and --S(O)2--C1-4
alkyl), Het1, --C(O)R5b, --N(H)R6,
--C(O)N(R8a)R5d, --OC(O)N(H)R8b, --S(O)2--C1-4
alkyl, --S(O)2N(H)R9c and --N(H)S(O)2R9d or R1
represents --C(O)OR7, --C(O)N(R8a)R5d or
--S(O)2--C1-5 alkyl;

[0112]Het1 represents a four- (e.g. five-) to ten-membered
heterocyclic group containing one to three heteroatoms selected from
oxygen, nitrogen and/or sulfur, which group is optionally substituted by
one or more (e.g. one to three) substituents selected from halo,
C1-3 alkyl, C1-3 alkoxy and --C(O)--C1-4 alkyl;

[0113]R5b, R5c and R5d independently represent H, C1-5
alkyl, phenyl (which latter group is optionally substituted by one or
more substituents selected from --OH, halo, cyano, pyrrolidin-1-yl,
C1-4 alkyl and C1-5 alkoxy (which latter group is optionally
substituted by one or more halo (e.g. fluoro) atoms)) or Het3;

[0114]Het3 represents a five- to ten-membered heterocyclic group
containing one or two heteroatoms selected from oxygen and nitrogen,
which group is optionally substituted by one or more substituents
selected from oxo, C1-2 alkyl and --C(O)--C1-4 alkyl;

[0115]R6 represents H, C1-4 alkyl, phenyl (which latter group is
optionally substituted by one or more cyano groups) or --C(O)O--C1-5
alkyl;

[0116]R7 represents C1-5 alkyl optionally substituted by
Het4;

[0117]Het4 represents a five- to ten-membered heterocyclic group
containing one or two heteroatoms selected from oxygen and nitrogen,
which group is optionally substituted by one or more substituents
selected from C1-2 alkyl and --C(O)--C1-4 alkyl;

[0118]R8a and R8b independently represent H, C1-5 alkyl or
-D-(phenyl), the phenyl part of which latter group is optionally
substituted by one or more (e.g. one to three) substituents selected from
halo, C1-3 alkyl and C1-3 alkoxy;

[0119]D represents C1-3 alkylene (e.g. CH2 or
C(CH3)2);

[0120]R9c and R9d independently represent C1-4 alkyl
(optionally substituted by one or more substituents selected from halo,
phenyl (which latter group is optionally substituted by one or more
substituents selected from halo, C1-2 alkyl and C1-2 alkoxy
(which latter two groups are optionally substituted by one or more halo
(e.g. fluoro) atoms)) and Het6), phenyl (which latter group is
optionally substituted by one or more substituents selected from halo,
C1-3 alkyl and C1-3 alkoxy (which latter two groups are
optionally substituted by one or more halo (e.g. fluoro) atoms)) or
Het7;

[0121]Het6 and Het7 independently represent four- (e.g. five-)
to ten-membered heterocyclic groups containing one to three heteroatoms
selected from oxygen, nitrogen and/or sulfur, which groups are optionally
substituted by one or more (e.g. one to three) substituents selected from
halo, C1-3 alkyl and C1-3 alkoxy;

[0122]R2 represents H, --OR13 or --N(H)R14;

[0123]R3 represents H;

[0124]R13 represents H or phenyl (which latter group is optionally
substituted by one or more substituents selected from cyano and C1-2
alkoxy);

[0125]R14 represents H phenyl (which latter group is optionally
substituted by one or more cyano groups) or --C(O)O--C1-5 alkyl;

[0129]R20b, together with a single R4 substituent at a position
on the phenyl or pyridyl group that is ortho- to the position at which
the group B is attached, represents C2-3 alkylene;

[0130]G represents CH;

[0131]R4 represents one or two cyano or halo (e.g. fluoro) groups in
the ortho- and/or, particularly, the para-position relative to the point
of attachment of the group B, or alternatively, when B represents
-Z-C(O)N(R20b)--, [0132](i) an R4 substituent in a position
on the phenyl or pyridyl group that is ortho- to the position at which
the group B is attached may, together with R20b, represent C2-3
alkylene, and [0133](ii) R4 may further represent a nitro group in
the para-position relative to the point of attachment of the group B.

[0134]Particularly preferred compounds of the invention include those in
which:

[0135]R1 represents straight- or branched-chain or part
cyclic/acyclic C1-6 alkyl, which alkyl group is optionally
interrupted by oxygen and/or substituted by: (i) one or more halo or
OR5c groups; and/or (ii) one group selected phenyl (which latter
group is optionally substituted by one or more (e.g. one to three)
substituents selected from halo, cyano, C1-2 alkyl, C1-2 alkoxy
(which latter two groups are optionally substituted by one or more halo
(e.g. fluoro) atoms), --C(O)--C1-2 alkyl and --S(O)2--C1-2
alkyl), Het1, --C(O)R5b, --N(H)R6, --C(O)N(H)R8a,
--OC(O)N(H)--C1-4 alkyl, --S(O)2--C1-4 alkyl,
--S(O)2N(H)--C1-4 alkyl and --N(H)S(O)2R9d;

[0136]Het1 represents a five- or six-membered heterocyclic group
containing one or two heteroatoms selected from oxygen, nitrogen and/or
sulfur, which group is optionally substituted by one or more (e.g. one or
two) substituents selected from halo (e.g. chloro), C1-2 alkyl and
C1-2 alkoxy;

[0137]R5b and R5c independently represent phenyl optionally
substituted by one to three substituents selected from halo, cyano,
C1-2 alkyl and C1-2 alkoxy;

[0138]R6 represents H, C1-4 alkyl or --C(O)O--C1-5 alkyl;

[0139]R8a represents C1-4 alkyl (e.g. tert-butyl) or
-D-(phenyl);

[0140]R9d represents C1-4 alkyl (optionally substituted by one
or more substituents selected from halo and phenyl (which latter group is
optionally substituted by one or more substituents selected from halo
(e.g. chloro), C1-2 alkyl and C1-2 alkoxy (which latter two
groups are optionally substituted by one or more halo (e.g. fluoro)
atoms))), phenyl (which latter group is optionally substituted by one or
more substituents selected from halo (e.g. fluoro), C1-2 alkyl and
C1-2 alkoxy (which latter two groups are optionally substituted by
one or more halo (e.g. fluoto) atoms)) or Het7;

[0141]Het7 represents a five- or six-membered heterocyclic group
containing one nitrogen atom and optionally containing one or two further
heteroatoms selected from oxygen, nitrogen and/or sulfur, which
heterocyclic group is optionally substituted by one to three substituents
selected from halo and C1-2 alkyl;

[0142]A represents --(CH2)1-2--;

[0143]B represents -Z-, --N(H)S(O)2-- (in which latter group, --N(H)
is attached to the carbon atom bearing R2 and R3),
--C(O)N(R20b)-- (in which latter group, --C(O) is attached to the
carbon atom bearing R2 and R3) or -Z-O-- (in which latter
group, Z is attached to the carbon atom bearing R2 and R3);

[0144]Z represents a direct bond or --(CH2)1-2--;

[0145]R20b, together with a single R4 substituent at a position
on the phenyl or pyridyl group that is ortho- to the position at which
the group B is attached, represents --(CH2)2-3--;

[0146]R4 represents a cyano or fluoro group in the para-position
relative to the point of attachment of the group B, and, when B
represents --C(O)N(R20b)--, R4 may also, together with
R20b, represent --(CH2)2-3--.

[0147]Especially preferred compounds of the invention include those in
which:

[0148]R1 represents straight- or branched-chain C1-3 alkyl
substituted by OR5c, phenyl (which latter group is optionally
substituted by one or two substituents selected from halo (e.g. fluoro or
chloro), cyano, methyl, methoxy (which latter two groups are optionally
substituted by one to three fluoro atoms), --C(O)CH3 and
--S(O)2CH3), Het1, --C(O)R5b, --N(H)C(O)O--C3-4
alkyl, --C(O)N(H)R8a, --OC(O)N(H)--C3-4 alkyl,
--S(O)2N(H)--C3-4 alkyl or --N(H)S(O)2R9d;

[0149]Het1 represents an aromatic five- or six-membered heterocyclic
group containing one or two heteroatoms selected from oxygen, nitrogen
and/or sulfur, which group is optionally substituted by one or two
substituents selected from chloro, methyl and methoxy;

[0150]R5b and R5c independently represent phenyl optionally
substituted by one or two substituents selected from cyano, methyl and
methoxy;

[0151]R8a represents tert-butyl, CH2-phenyl or
C(CH3)2-phenyl;

[0152]R9d represents C1-4 alkyl (which latter group is
optionally substituted by one or more fluoro atoms),
(CH2)1-2-phenyl (the phenyl part of which latter group is
optionally substituted by one to three substituents selected from chloro,
methyl and methoxy (which latter two groups are optionally substituted by
one or more fluoro atoms)), phenyl (optionally substituted by one or more
substituents selected from fluoro, methyl and methoxy (which latter two
groups are optionally substituted by one or more fluoro atoms)) or
Het7;

[0153]Het7 represents a five-membered heterocyclic group containing
one nitrogen atom and optionally containing one further heteroatom
selected from oxygen, nitrogen and sulfur, which heterocyclic group is
optionally substituted by one to three methyl groups;

[0154]R2 represents H or --OH;

[0155]A represents --CH2--;

[0156]B represents --CH2--, --N(H)S(O)2-- (in which latter
group, --N(H) is attached to the carbon atom bearing R2 and R3)
or --(CH2)0-1--O-- (in which latter group, --CH2-- is
attached to the carbon atom bearing R2 and R3).

[0157]Compounds of formula I that are more preferred still include those
in which: R1 represents [0158](i) C1-3 n-alkyl substituted by
phenyl (which latter group is optionally substituted by one to three
substituents selected from methyl and methoxy (which latter two groups
are optionally substituted by one to three (e.g. by two) fluoro atoms))
or phenoxy (the phenyl part of which latter group is optionally
substituted by cyano), [0159](ii) --N(H)C(O)O-tert-butyl, [0160](iii)
--S(O)2N(H)-tert-butyl or [0161](iv) --N(H)S(O)2R9d;

[0162]R9d represents [0163](a) methyl (optionally substituted by one
to three fluoro atoms), [0164](b) isopropyl, [0165](c) n-butyl, [0166](d)
-(CH2)-phenyl (the phenyl part of which latter group is optionally
substituted by one or two substituents selected from chloro, methyl and
trifluoromethyl), [0167](e) phenyl (which latter group is optionally
substituted by one or two substituents selected from fluoro, methoxy and
trifluoromethoxy) or (f) imidazolyl (e.g. imidazol-4-yl) or isoxazolyl
(e.g. isoxazol-4-yl), which latter two groups are optionally substituted
by one or two methyl groups.

[0168]Particular values of each variable group are as follows. Such values
may be used where appropriate with any of the values, definitions,
claims, aspects or embodiments defined hereinbefore or hereinafter. In
particular, each may be used as an individual limitation on the broadest
definition of formula (I). R1 represents C2-3 alkyl, which
alkyl group is substituted by at least one
--S(O)2N(R9b)R9c and/or --N(R9b)S(O)2R9d
group;

[0169]R9b, represents H or C1-3 alkyl;

[0170]R9c and R9d each independently represent hydrogen,
C1-6 alkyl (optionally substituted by one or more halo groups), aryl
(optionally substituted by one or more halo, cyano, methoxy,
fluoromethoxy, difluoromethoxy or trifluoromethoxy groups) or Het (such
as imidazolyl or isoxazolyl);

[0171]R2 and R3 each independently represent hydrogen, or
hydroxy;

[0172]A represents a direct bond or C1-3 alkylene;

[0173]B represents a direct bond, C1-3 alkylene or C1-3 alkoxy
(in which the oxygen is attached to the phenyl group that is optionally
substituted with R4);

[0174]G represents carbon;

[0175]R41 to R46 represents hydrogen; and

[0176]R4 represents one or more optional substituents selected from
cyano and/or halo (such as fluoro) and an R4 substituent is in a
position on the phenyl group that is ortho- and/or para- to the position
at which the group B is attached.

[0177]Particular compounds of the invention include, for example,
compounds of the Formula I, or pharmaceutically-acceptable salts thereof,
wherein, unless otherwise stated, each of each variable group has any of
the meanings defined hereinbefore or in paragraphs (a) to (d)
hereinafter:--

represents methylene, ethylene, propylene, butylene, or
2-hydroxypropylene, optionally terminated or interrupted with an oxygen
atom and/or optionally interrupted with a --SO2--NH-- or
--NH--SO2-- group; (d) the group

[0333]According to the invention there is also provided a process for the
preparation of compounds of formula I which comprises:

(a) reaction of a compound of formula II,

##STR00004##

wherein R2, R3, R4, R41 to R46, A, B and G are as
hereinbefore defined, with a compound of formula III,

R1-L1 III

wherein L1 represents a leaving group such as halo, alkanesulfonate,
perfluoroalkanesulfonate, arenesulfonate, --OC(O)XR7, Imidazole or
R23O--(wherein R23 represents, for example, Cl1-10 alkyl
or aryl, which groups are optionally substituted by one or more halo or
nitro groups) and X, R1 and R7 are as hereinbefore defined, for
example at between room and reflux temperature in the presence of a
suitable base (e.g. triethylamine, potassium carbonate or a bicarbonate,
such as sodium bicarbonate) and an appropriate solvent (e.g.
dichloromethane, chloroform, acetonitrile, N,N-dimethylformamide, THF,
toluene, water, a lower alkyl alcohol (e.g. ethanol) or mixtures
thereof);(b) for compounds of formula I in which R1 represents
C1-12 alkyl substituted by one or more substituents as defined above
in respect of R1, which substituent(s) is/include a
--N(R9b)S(O)2R9d group, reaction of a compound of formula
IV,

##STR00005##

wherein R1a represents C1-12 alkylene, which group is optionally
substituted by one or more substituents as defined above in respect of
R1, and R2, R3, R4, R41 to R46, A, B and G
are as hereinbefore defined, with a compound of formula V,

L2-S(O)2R9d V

wherein L2 represents a suitable leaving group such as halo and
R9d is as hereinbefore defined, for example under conditions that
are know to those skilled in the art (e.g. at ambient temperature (such
as from 15 to 30° C.) in the presence of a suitable base (such as
such as triethylamine, potassium carbonate or sodium hydrogencarbonate)
and an appropriate solvent (such as DCM, CHCl3, acetonitrile, DMF,
THF, toluene, or mixtures thereof);(c) for compounds of formula I in
which R1 represents C1-12 alkyl substituted by one or more
substituents as defined above in respect of R1, which substituent(s)
is/include a --S(O)2N(R9b)R9c group, reaction of a
compound of formula II, as hereinbefore defined, with a compound of
formula VA,

L1-R1a--SO2--N(R9b)R9c VA

wherein L1, R1a, R9b and R9c are as hereinbefore
defined, for example under conditions that are know to those skilled in
the art (e.g. at ambient temperature to reflux in the presence of a
suitable base (such as such as triethylamine, potassium carbonate or
sodium hydrogencarbonate) and an appropriate solvent (such as DCM,
CHCl3, acetonitrile, DMF, THF, toluene, or mixtures thereof);(d) for
compounds of formula I in which R1 represents --C(O)XR7 or
--C(O)N(R8a)R5d, reaction of a compound of formula VI,

##STR00006##

wherein R2, R3, R4, R41 to R46, A, B, G and
L1 are as hereinbefore defined, with a compound of formula VII,

R24--H VII

wherein R24 represents --XR7 or --N(R8a)R5d and
R5d, R7, R8a and X are as hereinbefore defined, for
example under similar conditions to those described hereinbefore (process
step (a));(e) for compounds of formula I in which R1 represents
--C(O)N(H)R8a, reaction of a compound of formula II, as hereinbefore
defined, with a compound of formula VIII,

R8a--N═C═O VIII

wherein R8a is as hereinbefore defined, for example at between
0° C. and reflux temperature in the presence of an appropriate
organic solvent (e.g. dichloromethane), or via solid phase synthesis
under conditions known to those skilled in the art;(f) reaction of a
compound of formula IX,

##STR00007##

wherein R1 and R41 to R46 are as hereinbefore defined, with
a compound of formula X,

##STR00008##

wherein L3 represents a leaving group such as halo, alkanesulfonate
(e.g. mesylate), perfluoroalkanesulfonate or arenesulfonate (e.g. 2- or
4-nitrobenzenesulfonate, toluenesulfonate or benzenesulfonate) and
R2, R3, R4, A, B and G are as hereinbefore defined, for
example at elevated temperature (e.g. between 35° C. and reflux
temperature) in the presence of a suitable base (e.g. triethylamine or
potassium carbonate) and an appropriate organic solvent (e.g.
acetonitrile, dichloromethane, chloroform, dimethylsulfoxide,
N,N-dimethylformamide, a lower alkyl alcohol (e.g. ethanol), isopropyl
acetate or mixtures thereof);(g) for compounds of formula I in which B
represents -Z-N(R20c)S(O)2--, reaction of a compound of formula
IX, as hereinbefore defined, with a compound of formula XA,

##STR00009##

wherein R2, R3, R4, A, G, Z and L3 are as hereinbefore
defined, for example under conditions described in respect of process (f)
above;(h) for compounds of formula I in which A represents CH2 and
R2 represents --OH or --N(H)R14, reaction of a compound of
formula IX, as hereinbefore defined, with a compound of formula XI,

##STR00010##

wherein Y represents O or N(R14) and R3, R4, R14, B
and G are as hereinbefore defined, for example at elevated temperature
(e.g. 60° C. to reflux) in the presence of a suitable solvent
(e.g. a lower alkyl alcohol (e.g. IPA), acetonitrile, or a mixture of a
lower alkyl alcohol and water);(i) for compounds of formula I in which B
represents -Z-O--, reaction of a compound of formula XII,

##STR00011##

wherein R1, R2, R3, R41 to R46, A and Z are as
hereinbefore defined, with a compound of formula XIII,

##STR00012##

wherein R4 and G are as hereinbefore defined, for example under
Mitsunobu-type conditions e.g. at between ambient (e.g. 25° C.)
and reflux temperature in the presence of a tertiary phosphine (e.g.
tributylphosphine or triphenylphosphine), an azodicarboxylate derivative
(e.g. diethylazodicarboxylate or 1,1'-(azodicarbonyl)dipiperidine) and an
appropriate organic solvent (e.g. dichloromethane or toluene);(j) for
compounds of formula I in which G represents N and B represents -Z-O--,
reaction of a compound of formula XII, as hereinbefore defined, with a
compound of formula XIV,

##STR00013##

wherein R4 and L3 are as hereinbefore defined, for example at
between 10° C. and reflux temperature in the presence of a
suitable base (e.g. sodium hydride) and an appropriate solvent (e.g.
N,N-dimethylformamide);(k) for compounds of formula I in which R2
represents --OR3, in which R13 represents C1-6 alkyl,
-E-aryl or -E-Het8, reaction of a compound of formula I in which
R2 represents OH with a compound of formula XV,

R13aOH XV

wherein R13a represents C1-6 alkyl, -E-aryl or -E-Het8 and
E and Het8 are as hereinbefore defined, for example under
Mitsunobu-type conditions (e.g. as described hereinbefore in process step
(h));(1) for compounds of formula I in which R2 represents
--OR3, in which R13 represents C1-6 alkyl, -E-aryl or
-E-Het8, reaction of a compound of formula XVI,

##STR00014##

wherein R1, R3, R4, R41 to R46, A, B, G and
L3 are as hereinbefore defined, with a compound of formula XV, as
hereinbefore defined, for example at between ambient (e.g. 25° C.)
and reflux temperature, under Williamson-type conditions (i.e. in the
presence of an appropriate base (e.g. KOH or NaH) and a suitable organic
solvent (e.g. dimethylsulfoxide or N,N-dimethyl-formamide)) (the skilled
person will appreciate that certain compounds of formula XVI (e.g. those
in which L3 represents halo) may also be regarded as compounds of
formula I as hereinbefore defined);(m) for compounds of formula I in
which R2 represents -E-NH2, reduction of a compound of formula
XVII,

##STR00015##

wherein R1, R3, R4, R41 to R46, A, B, E and G are
as hereinbefore defined, for example by hydrogenation at a suitable
pressure in the presence of a suitable catalyst (e.g. palladium on
carbon) and an appropriate solvent (e.g. a water-ethanol mixture);(n) for
compounds of formula I in which R2 represents
-E-N(R14)R15, wherein R14 represents C1-6 alkyl,
-E-aryl -E-Het9, --C(O)R16a, --C(O)OR16b,
--S(O)2R16c or --C(O)N(R17a)R17b, reaction of a
compound of formula I in which R2 represents -E-N(H)R15 with a
compound of formula XVIII,

R17a-L1 XVIII

wherein R14a represents C1-6 alkyl, -E-aryl -E-Het9,
--C(O)R16a, --C(O)OR16b, --S(O)2R16c or
--C(O)N(R17a)R17b, and R16a, R16b, R16c,
R17a, R17b, Het9, E and L1 are as hereinbefore
defined, for example under conditions described hereinbefore (process
step (a));(o) for compounds of formula I in which R2 represents
-E-N(R15)C(O)N(H)R17a, reaction of a compound of formula I in
which R2 represents -E-N(H)R15 with a compound of formula XIX,

R17aN═C═O XIX

wherein R17 is as hereinbefore defined, for example under conditions
described hereinbefore (process step (e));(p) for compounds of formula I
in which R2 represents -E-N(H)[C(O)]2NH2, reaction of a
compound of formula I in which R2 represents -E-NH2 with oxalic
acid diamide, for example at between -10 and 25° C. in the
presence of a suitable coupling agent (e.g.
1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide), an appropriate
activating agent (e.g. 1-hydroxybenzotriazole), a suitable base (e.g.
triethylamine) and a reaction-inert solvent (e.g.
N,N-dimethylformamide);(q) for compounds of formula I in which R2
represents -E-N(H)C(NH)NH2, reaction of a compound of formula I in
which R2 represents -E-NH2 with a compound of formula XX,

R23O--C(═NH)NH2 XX

or an N-protected derivative thereof, wherein R23 is as hereinbefore
defined, for example at between room and reflux temperature, optionally
in the presence of a suitable solvent (e.g. toluene) and/or an
appropriate acidic catalyst (e.g. acetic acid at, for example, 10 mol
%);(r) for compounds of formula I in which R2 represents
--OR13, in which R13 represents --C(O)R16a,
--C(O)OR16b or --C(O)N(R17a)R17b, reaction of a compound
of formula I in which R2 represents --OH with a compound of formula
XX1,

R13b-L4 XXI

wherein R13b represents --C(O)R16a, --C(O)OR16b or
--C(O)N(R17a)R17b, L4 represents a leaving group such as
halo, p-nitrophenoxy, --OC(O)R16a, --OC(O)OR16b, --OH or
imidazole and R16a, R16b, R17a and R17b are as
hereinbefore defined, for example at between -10° C. and reflux
temperature in the presence of a suitable base (e.g. triethylamine,
pyridine or potassium carbonate), an appropriate organic solvent (e.g.
THF, dichloromethane or acetonitrile) and (where appropriate) a suitable
coupling agent (e.g. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide);(s)
for compounds of formula I in which R2 represents H or --OH and
R3 represents H, reduction of a compound of formula I in which
R2 and R3 together represent ═O, in the presence of a
suitable reducing agent and under appropriate reaction conditions; for
example, for formation of compounds of formula I in which R2
represents OH, reduction may be performed under mild reaction conditions
in the presence of e.g. sodium borohydride and an appropriate organic
solvent (e.g. THF); for formation of compounds of formula I in which
R2 represents OH, wherein the compound is enantiomerically enriched
(or is a single enantiomer) at the chiral centre to which R2 is
attached, reduction may be performed enzymatically (for example under
conditions known to those skilled in the art, such as in the presence of
horse liver alcohol dehydrogenase and NADPH) or by hydrogenation in the
presence of a suitable solution-phase (homogeneous) catalyst under
conditions known to those skilled in the art; and for formation of
compounds of formula I in which R2 represents H, reduction may be
performed either under Wolff-Kischner conditions known to those skilled
in the art or by activating the relevant C═O group using an
appropriate agent (such as tosylhydrazine) in the presence of a suitable
reducing agent (e.g. sodium borohydride or sodium cyanoborohydride) and
an appropriate organic solvent (e.g. a lower (e.g. C1-6) alkyl
alcohol);(t) for compounds of formula I in which R2 represents halo,
substitution of a corresponding compound of formula I in which R2
represents --OH, using an appropriate halogenating agent (e.g. for
compounds in which R2 represents fluoro, reaction with
(diethylamino)sulfur trifluoride);(u) for compounds of formula I in which
R2 and R3 represent H, A represents -J- and B represents
--N(R20e)-Z- (wherein --N(R20e) is attached to the carbon atom
bearing R2 and R3), reaction of a compound of formula XXII,

##STR00016##

wherein R1, R20e, R41 to R46 and J are as hereinbefore
defined, with a compound of formula XXIII,

##STR00017##

wherein R4, G, Z and L3 are as hereinbefore defined, for example
at elevated temperature (e.g. 40° C. to reflux) in the presence of
a suitable organic solvent (e.g. acetonitrile);(v) for compounds of
formula I in which A represents --(CH2)2-- and R2 and
R3 together represent ═O, reaction of a compound of formula IX,
as hereinbefore defined, with a compound of formula XXIV,

##STR00018##

wherein B, G and R4 are as hereinbefore defined, for example at
between room and reflux temperature in the presence of a suitable base
(e.g. triethylamine, potassium carbonate or tetrabutylammonium hydroxide)
and an appropriate organic solvent (e.g. a lower alkyl (e.g. C1-6)
alcohol);(w) for compounds of formula I in which R1 represents
--C(O)XR7, --C(O)N(R8a)R5d or --S(O)2R9a,
reaction of a compound of formula XXV,

##STR00019##

wherein R1b represents --C(O)XR7, --C(O)N(R8a)R5b or
--S(O)2R9a and R5d, R7, R8a, R9a, R41
to R46 and L are as hereinbefore defined, with a compound of formula
XXVI,

##STR00020##

wherein R2, R3, R4, A, B and G are as hereinbefore defined,
for example at between room and reflux temperature in the presence of a
suitable base (e.g. sodium hydrogencarbonate or potassium carbonate) and
an appropriate organic solvent (e.g. acetonitrile);(x) for compounds of
formula I which are oxabispidine-nitrogen N-oxide derivatives, oxidation
of the corresponding oxabispidine nitrogen of a corresponding compound of
formula I, in the presence of a suitable oxidising agent (e.g. mCPBA),
for example at 0° C. in the presence of a suitable organic solvent
(e.g. dichloromethane);(y) for compounds of formula I which are C1-4
alkyl quaternary ammonium salt derivatives, in which the alkyl group is
attached to a oxabispidine nitrogen, reaction, at the oxabispidine
nitrogen, of a corresponding compound of formula I with a compound of
formula XXVII,

R25-L5 XXVII

wherein R25 represents C1-4 alkyl and L5 is a leaving group
such as halo, alkanesulfonate or arenesulfonate, for example at room
temperature in the presence of an appropriate organic solvent (e.g.
N,N-dimethylformamide), followed by purification (using e.g. HPLC) in the
presence of a suitable counter-ion provider (e.g. NH4OAc);(z)
conversion of one R4 substituent to another using techniques well
known to those skilled in the art; or(aa) introduction of one or more
(further) R4 substituents to the aromatic ring using techniques well
known to those skilled in the art (e.g. chlorination).(ab) for compounds
of formula I in wherein R1 represents C1-12 alkylene, which
group is optionally substituted by one or more substituents as defined
above in respect of R1, reaction of a compound of formula II

##STR00021##

wherein R2, R3, R4, R41 to R46, A, B and G are as
hereinbefore defined, with the appropriate aldehyde, for example under
conditions that are known to those skilled in the art (e.g. at room
temperature, such as from 15 to 30° C.) in the presence of a
reducing agent (such as sodium cyanoborohydride, sodium
triacetoxyborohydride, or similar compounds) and an appropriate solvent
(such as 1,2-dichloroethane, dichloroethane, methanol, ethanol or
mixtures thereof);(ac) for compounds of formula I in wherein A represents
-J-, -J-N(R19a)--, -J-S(O)2N(R19b)--,
-J-N(R19c)S(O)2-- or -J-O-- (in which latter four groups, -J is
attached to the oxabispidine ring nitrogen), reaction of a compound with
formula VII

##STR00022##

wherein R1 and R41 to R46 are as hereinbefore defined, with
a compound of formula XXIII

##STR00023##

wherein R2, R4, B and G are as hereinbefore defined and the
C0-5 alkylene group is optionally substituted by one or more
substituents as defined above in respect of J, for example under
conditions that are known to those skilled in the art (e.g. at room
temperature, such as from 15 to 30° C.) in the presence of a
reducing agent (such as sodium cyanoborohydride, sodium
triacetoxyborohydride, or similar hydride donating compounds) and an
appropriate solvent (such as 1,2-dichloroethane, dichloroethane,
methanol, ethanol or mixtures thereof); or(ad) deprotection of a
protected derivative of a compound of formula I as defined above.

[0334]Compounds of formulae II, IV, IX, X, XI, XII, XVI, XVII, XXII and
XXV may be prepared according to or by analogy with the procedures
described or referred to in WO 01/28992, WO 02/28863, WO 02/28864, WO
02/83690 and WO 02/83691, the disclosures of which documents are hereby
incorporated by reference.

[0335]Compounds of formula VA may be prepared by reaction of a compound of
formula XXVIII,

HN(R9b)R9c XXVIII

wherein R9b and R9c are as hereinbefore defined, with a compound
of formula XXIX,

L1-R1a--SO2-L2 XXIX

wherein L1, L2 and R1a are as hereinbefore defined, for
example under conditions known to those skilled in the art (e.g. those
described in respect of process (b) above).

[0336]Compounds of formula XA may be prepared by reaction of a compound of
formula XXX,

L2-SO2-A-L3 XXX

wherein A, L2 and L3 are as hereinbefore defined, with a
compound of formula XXXI,

##STR00024##

wherein R4, G and Z are as hereinbefore defined, for example under
conditions known to those skilled in the art (e.g. those described in
respect of process (b) above).

[0337]Compounds of formulae III, V, VII, VIII, XIII, XIV, XV, XVIII, XIX,
XX, XXI, XXIII, XXIV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI and
derivatives thereof, are either commercially available, are known in the
literature, or may be obtained either by analogy with the processes
described herein, or by conventional synthetic procedures, in accordance
with standard techniques, from readily available starting materials using
appropriate reagents and reaction conditions.

[0338]Substituents on the aryl (e.g. phenyl), and (if appropriate)
heterocyclic, group(s) in compounds defined herein may be converted to
other claimed substituents using techniques well known to those skilled
in the art. For example, hydroxy may be converted to alkoxy, phenyl may
be halogenated to give halophenyl, nitro may be reduced to give amino,
halo may be displaced by cyano, etc.

[0339]The skilled person will also appreciate that various standard
substituent or functional group interconversions and transformations
within certain compounds of formula I will provide other compounds of
formulae I. For example, carbonyl may be reduced to hydroxy or alkylene,
and hydroxy may be converted to halo.

[0340]The compounds of the invention may be isolated from their reaction
mixtures using conventional techniques.

[0341]It will be appreciated by those skilled in the art that, in the
process described above, the functional groups of intermediate compounds
may be, or may need to be, protected by protecting groups.

[0343]The protection and deprotection of functional groups may take place
before or after any of the reaction steps described hereinbefore.
Protecting groups may be removed in accordance with techniques which are
well known to those skilled in the art and as described hereinafter.

[0345]Persons skilled in the art will appreciate that, in order to obtain
compounds of the invention in an alternative, and, on some occasions,
more convenient, manner, the individual process steps mentioned herein
may be performed in a different order, and/or the individual reactions
may be performed at a different stage in the overall route (i.e.
substituents may be added to and/or chemical transformations performed
upon, different intermediates to those associated hereinbefore with a
particular reaction). This will depend inter alia on factors such as the
nature of other functional groups present in a particular substrate, the
availability of key intermediates and the protecting group strategy (if
any) to be adopted. Clearly, the type of chemistry involved will
influence the choice of reagent that is used in the said synthetic steps,
the need, and type, of protecting groups that are employed, and the
sequence for accomplishing the synthesis.

[0346]It will also be appreciated by those skilled in the art that,
although certain protected derivatives of compounds of formula I, which
may be made prior to a final deprotection stage, may not possess
pharmacological activity as such, they may be administered parenterally
or orally and thereafter metabolised in the body to form compounds of the
invention which are pharmacologically active. Such derivatives may
therefore be described as "prodrugs". Moreover, certain compounds of
formula I may act as prodrugs of other compounds of formula I.

[0347]All prodrugs of compounds of formula I are included within the scope
of the invention.

[0348]Some of the intermediates referred to hereinbefore are novel.
According to a further aspect of the invention there is thus provided:

(a) a compound of formula II, as hereinbefore defined, or a protected
derivative thereof, provided that [0349](i) A represents
-J-S(O)2N(R19b)-- or -J-N(R19c)S(O)2--, [0350](ii) J
is interrupted by --S(O)2N(R19d)-- or
--N(R19e)S(O)2--, [0351](iii) B represents
-Z-N(R2c)S(O)2--, -Z-S(O)2N(R2d)--,
--N(R20f)S(O)2-Z- or --S(O)2N(R20gl )-Z- and/or
[0352](iv) Z is interrupted by --N(R20i)S(O)2-- or
--S(O)2N(R20i)--;(b) a compound of formula IV, as hereinbefore
defined, or a protected derivative thereof, provided that [0353](i) A
represents -J-S(O)2N(R19b)-- or -J-N(R19c)S(O)2--,
[0354](ii) J is interrupted by --S(O)2N(R19d)-- or
--N(R19e)S(O)2--, [0355](iii) B represents
-Z-N(R20c)S(O)2--, -Z-S(O)2N(R20d)--,
--N(R20)S(O)2-Z- or --S(O)2N(R20g)-Z- and/or
[0356](iv) Z is interrupted by --N(R20i)S(O)2-- or
--S(O)2N(R20j)--;(c) a compound of formula VI, as hereinbefore
defined, or a protected derivative thereof, provided that [0357](i) A
represents -J-S(O)2N(R19b)-- or -J-N(R19c)S(O)2--,
[0358](ii) J is interrupted by --S(O)2N(R9d)-- or
--N(R19e)S(O)2--, [0359](iii) B represents
-Z-N(R20c)S(O)2--, -Z-S(O)2N(R21d)--,
--N(R20f)S(O)2-Z- or --S(O)2N(R20g)-Z- and/or
[0360](iv) Z is interrupted by --N(R20i)S(O)2-- or
--S(O)2N(R20j)--;(d) a compound of formula IX, as hereinbefore
defined, or a protected derivative thereof, provided that R1
represents C1-12 alkyl (which alkyl group is substituted by one or
more groups including at least one --S(O)2N(R9b)R9c and/or
--N(R9b)S(O)2R9d group);(e) a compound of formula X, as
hereinbefore defined, or a protected derivative thereof, provided that
[0361](i) A represents -J-S(O)2N(R19b)-- or
-J-N(R9c)S(O)2--, [0362](ii) J is interrupted by
--S(O)2N(R19d)-- or --N(R19e)S(O)2--, [0363](iii) B
represents -Z-N(R20c)S(O)2--, -Z-S(O)2N(R20d)--,
--N(R20g)S(O)2-Z- or --S(O)2N(R21g)-Z- and/or
[0364](iv) Z is interrupted by --N(R20i)S(O)2-- or
--S(O)2N(R20j)--;(f) a compound of formula XI, as hereinbefore
defined, or a protected derivative thereof, provided that [0365](i) B
represents -Z-N(R20c)S(O)2--, -Z-S(O)2N(R20d)--,
--N(R20f)S(O)2-Z- or --S(O)2N(R20g)-Z- and/or
[0366](ii) Z is interrupted by --N(R20i)S(O)2-- or
--S(O)2N(R20j)--;(g) a compound of formula XII, as hereinbefore
defined, or a protected derivative thereof, provided that [0367](i)
R1 represents C1-12 alkyl (which alkyl group is substituted by
one or more groups including at least one --S(O)2N(R9b)R9c
and/or --N(R9b)S(O)2R9d group), [0368](ii) A represents
-J-S(O)2N(R19b)-- or -J-N(R19c)S(O)2--, and/or
[0369](iii) J is interrupted by --S(O)2N(R19d)-- or
--N(R19e)S(O)2--;(h) a compound of formula XVII, as
hereinbefore defined, or a protected derivative thereof, provided that
[0370](i) R1 represents C1-12 alkyl (which alkyl group is
substituted by one or more groups including at least one
--S(O)2N(R9b)R9c and/or --N(R9b)S(O)2R9d
group), [0371](ii) A represents -J-S(O)2N(R19b)-- or
-J-N(R19c)S(O)2--, [0372](iii) J is interrupted by
--S(O)2N(R9d)-- or --N(R19e)S(O)2--, [0373](iv) B
represents -Z-N(R20c)S(O)2--, -Z-S(O)2N(R20d)--,
--N(R20f)S(O)2-Z- or --S(O)2N(R20g)-Z- and/or
[0374](v) Z is interrupted by --N(R20i)S(O)2-- or
--S(O)2N(R20j)--;(i) a compound of formula XXII, as
hereinbefore defined, or a protected derivative thereof, provided that
[0375](i) R1 represents C1-12 alkyl (which alkyl group is
substituted by one or more groups including at least one
--S(O)2N(R9b)R9c and/or --N(R9b)S(O)2R9d
group), and/or [0376](ii) J is interrupted by --S(O)2N(R19d)--
or --N(R19e)S(O)2--;(j) a compound of formula XXII, as
hereinbefore defined, or a protected derivative thereof, provided that
[0377](i) B represents -Z-N(R20c)S(O)2--,
-Z-S(O)2N(R20d)--, --N(R20f)S(O)2-Z- or
--S(O)2N(R20g)-Z- and/or [0378](ii). Z is interrupted by
--N(R20i)S(O)2-- or --S(O)2N(R20j)--;(k) a compound
of formula XXIV, as hereinbefore defined, or a protected derivative
thereof, provided that [0379](i) B represents
-Z-N(R20c)S(O)2--, -Z-S(O)2N(R20d)--,
--N(R20f)S(O)2-Z- or --S(O)2N(R20g)-Z- and/or
[0380](ii) Z is interrupted by --N(R20i)S(O)2-- or
--S(O)2N(R20j)--; and(l) a compound of formula XXVI, as
hereinbefore defined, or a protected derivative thereof, provided that
[0381](i) A represents -J-S(O)2N(R19b) or
-J-N(R19c)S(O)2, [0382](ii) J is interrupted by
--S(O)2N(R19d)-- or --N(R19e)S(O)2--, [0383](iii) B
represents -Z-N(R20c)S(O)2--, -Z-S(O)2N(R20d)--,
--N(R20)S(O)2-Z- or --S(O)2N(R20g)-Z- and/or
[0384](iv) Z is interrupted by --N(R20i)S(O)2-- or
--S(O)2N(R21j)--.

Medical and Pharmaceutical Use

[0385]Compounds of the invention are useful because they possess
pharmacological activity. They are therefore indicated as
pharmaceuticals.

[0386]Thus, according to a further aspect of the invention there is
provided the compounds of the invention for use as pharmaceuticals.

[0387]In particular, the compounds of the invention exhibit myocardial
electrophysiological activity, for example as demonstrated in the test
described below.

[0388]The compounds of the invention are thus expected to be useful in
both the prophylaxis and the treatment of arrhythinias, and in particular
atrial and ventricular arrhythmias.

[0389]The compounds of the invention are thus indicated in the treatment
or prophylaxis of cardiac diseases, or in indications related to cardiac
diseases, in which arrhythmias are believed to play a major role,
including ischaemic heart disease, sudden heart attack, myocardial
infarction, heart failure, cardiac surgery and thromboembolic events.

[0390]In the treatment of arrhythmias, compounds of the invention have
been found to selectively delay cardiac repolarization and increase
refractoriness.

[0391]According to a further aspect of the invention, there is provided a
method of treatment of an arrhythmia which method comprises
administration of a therapeutically effective amount of a compound of the
invention to a person suffering from, or susceptible to, such a
condition.

Pharmaceutical Preparations

[0392]The compounds of the invention will normally be administered orally,
subcutaneously, intravenously, intraarterially, transdermally,
intranasally, by inhalation, or by any other parenteral route, in the
form of pharmaceutical preparations comprising the active ingredient
either as a free base or a non-toxic organic or inorganic acid addition
salt, in a pharmaceutically acceptable dosage form. Depending upon the
disorder and patient to be treated, as well as the route of
administration, the compositions may be administered at varying doses.

[0393]The compounds of the invention may also be combined with any other
drugs useful in the treatment of arrhythmias and/or other cardiovascular
disorders. In particular the compounds of the invention may be combined
with an anti-coagulant.

[0395]Particular anticoagulants that may be mentioned include aspirin and
warfarin.

[0396]The term "an anticoagulant" also includes references to thrombin
inhibitors. Thrombin inhibitors that may be mentioned include low
molecular weight thrombin inhibitors. The term "low molecular weight
thrombin inhibitors" will be understood by those skilled in the art, and
includes references to any composition of matter (e.g. chemical compound)
that inhibits thrombin to an experimentally determinable degree (as
determined by in vivo and/or in vitro tests), and which possesses a
molecular weight of below about 2,000, preferably below about 1,000.

[0399]In the present application, derivatives of thrombin inhibitors
include chemical modifications, such as esters, prodrugs and metabolites,
whether active or inactive, and pharmaceutically acceptable salts and
solvates, such as hydrates, of any of these, and solvates of any such
salt.

[0400]Preferred low molecular weight peptide-based thrombin inhibitors
include those known collectively as the "gatrans". Particular gatrans
which may be mentioned include HOOC--CH2--(R)Cha-Pic-Nag-H (known as
inogatran) and HOOC--CH2--(R)Cgl-Aze-Pab-H (known as melagatran)
(see International Patent Application WO 93/11152 and WO 94/29336,
respectively, and the lists of abbreviations contained therein).

[0401]International Patent Application WO 97/23499 discloses a number of
compounds which have been found to be useful as prodrugs of thrombin
inhibitors. Said prodrugs have the general formula

[0402]According to a further aspect of the invention there is thus
provided a pharmaceutical formulation including a compound of the
invention in admixture with a pharmaceutically acceptable adjuvant,
diluent or carrier.

[0403]Suitable daily doses of the compounds of the invention in
therapeutic treatment of humans are about 0.005 to 50.0 mg/kg body weight
at oral administration and about 0.005 to 15.0 mg/kg body weight at
parenteral administration. Preferable ranges of daily doses of the
compounds of the invention in therapeutic treatment of humans are about
0.005 to 20.0 mg/kg body weight at oral administration and about 0.005 to
10.0 mg/kg body weight at parenteral administration.

[0404]The compounds of the invention have the advantage that they are
effective against cardiac arrhythmias.

[0405]Compounds of the invention may also have the advantage that they may
be more efficacious than, be less toxic than, have a broader range of
activity (including exhibiting any combination of class I, class II,
class III and/or class IV activity (especially class I and/or class IV
activity in addition to class III activity)) than, be more potent than,
be longer acting than, produce fewer side effects (including a lower
incidence of proarrhythmias such as torsades de pointes) than, be more
easily absorbed than, or that they may have other useful pharmacological
properties over, compounds known in the prior art.

Biological Tests

Test A

Primary Electrophysiological Effects In Anaesthetised Guinea Pigs

[0406]Guinea pigs weighing between 500 and 1000 g were used. The animals
were housed for at least one week before the experiment and had free
access to food and tap water during that period.

[0407]Anaesthesia was induced by an intraperitoneal injection of
pentobarbital (50 to 60 mg/kg) and catheters were introduced into one
carotid artery (for blood pressure recording and blood sampling) and into
one jugular vein (for drug infusions). Needle electrodes were placed on
the limbs for recording of ECGs (lead II). A thermistor was placed in the
rectum and the animal was placed on a heating pad, set to a rectal
temperature of between 37.5 and 38.5° C.

[0408]A tracheotomy was performed and the animal was artificially
ventilated with room air by use of a small animal ventilator, set to keep
blood gases within the normal range for the species. In order to reduce
autonomic influences both vagi were cut in the neck, and 0.5 mg/kg of
propranolol was given intravenously, 15 minutes before the start of the
experiment.

[0409]The left ventricular epicardium was exposed by a left-sided
thoracotomy, and a custom-designed suction electrode for recording of the
monophasic action potential (MAP) was applied to the left ventricular
free wall. The electrode was kept in position as long as an acceptable
signal could be recorded, otherwise it was moved to a new position. A
bipolar electrode for pacing was clipped to the left atrium. Pacing (1 ms
duration, twice the diastolic threshold) was performed with a custom-made
constant current stimulator. The heart was paced at a frequency just
above the spontaneous sinus rate during 30 s every fifth minute
throughout the study.

[0410]The MAP signal, the blood pressure signal and the lead II ECG were
collected (the sampling frequency was 1000 Hz and each sampling period 10
s) on a personal computer during the last 10 s of each 30 s pacing
sequence and the last 10 s of the following min of sinus rhythm. The
signals were processed using a custom-designed computer program (PharmLab
v 4.0).

[0411]The test procedure consisted of two basal control recordings, 3
minutes apart, during both pacing and sinus rhythm. After the second
control recording, the first dose of the test substance was infused in a
volume of 0.2 mL/kg into the jugular vein catheter for 30 seconds. Three
minutes later, pacing was started and a new recording was made. Five
minutes after the previous dose, the next dose of test substance was
administered. Six to ten consecutive doses were given during each
experiment.

Data Analysis

[0412]Of the numerous variables measured in this analysis, three were
selected as the most important for comparison and selection of active
compounds. The three variables selected were the MAP duration at 75
percent repolarization during pacing, the atrio-ventricular (AV)
conduction time (defined as the interval between the atrial pace pulse
and the start of the ventricular MAP) during pacing, and the heart rate
(defined as the RR interval during sinus rhythm). Systolic and diastolic
blood pressure were measured in order to judge the haemodynamic status of
the anaesthetised animal. Further, the ECG was checked for arrhythmias
and/or morphological changes.

[0413]The mean of the two control recordings was set to zero and the
effects recorded after consecutive doses of test substance were expressed
as percentage changes from this value. By plotting these percentage
values against the cumulative dose administered before each recording, it
was possible to construct dose-response curves. In this way, each
experiment generated three dose-response curves, one for MAP duration,
one for AV-conduction time and one for the sinus frequency (RR interval).
A mean curve of all experiments performed with a test substance was
calculated, and potency values were derived from the mean curve. All
dose-response curves in these experiments were constructed by linear
connection of the data points obtained. The cumulative dose prolonging
the MAP duration by 10% from the baseline was used as an index to assess
the class III electrophysiological potency of the agent under
investigation (D10).

[0416]Cells were grown in Ham F12 (Life Technologies 31765-027)
supplemented with 10% FBS and 0.6 mg/mL hygromycin B and were routinely
passaged twice-weekly. For experimental studies, cells were plated at a
density of 15,000 cells/well in Falcon, 384-well tissue culture-treated
black-walled clear-bottomed plates and were thereafter incubated
overnight at 37° C. in a cell culture incubator.

[0417]Following incubating overnight, cell plates were washed and a
Rb+-Load buffer (a physiological buffer containing Rb+) was
added. Cell plates were then incubated for 3 hours and were thereafter
washed. Following this wash, the test compounds were added. The cell
plates were then incubated for another 10 minutes and, following this
incubation period, external K+ concentration was increased in order
to depolarize the cells and activate HERG channels. After a ten minute
exposure period to the increased K+ concentration, supernatants were
transferred to new microplates for subsequent determination of Rb+
content, using Atomic Absorption Spectrometry analysis.

[0418]The basal Rb+ efflux (content of Rb+ (mg/L) in
supernatants of wells receiving only wash buffer) was defined as 100%
inhibition and the stimulated Rb+ efflux (content of Rb+ (mg/L)
in supernatants of wells exposed only to increased external potassium
concentration) was defined as 0% inhibition.

[0426]The mass spectra were recorded with a Waters ZQ2000 or Waters ZMD
equipped with an electrospray interface, switching positive and negative
ionization mode. UV spectra were collected by a Agilent 1100 PDA or
Waters 2996 DAD and the evaporative light scattering (ELS ) signal by a
Sedere Sedex 55 or 75.

[0427]Data collection and evaluation were performed using the MassLynx
software.

1H NMR and 13C NMR measurements were performed on a BRUKER ACP
300 and Varian 300, 400, 500 and 600 Mercury, Unity plus and Inova
spectrometers, operating at 1H frequencies of 300, 400, 500 and 600
MHz respectively and at 13C frequencies of 75.4, 100.6, 125.7 and
150.9 MHz respectively.

[0429]Rotamers may or may not be denoted in spectra depending upon ease of
interpretation of spectra. Unless otherwise stated, chemical shifts are
given in ppm with the solvent as internal standard.

Synthesis of Intermediates

[0430]The following intermediates were not commercially available, and
were therefore prepared by the methods described below.

[0431]tert-Butyl
2-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-di-azabicyclo[3.-
3.1]non-3-yl}ethylcarbamate (2.9 g, 6.56 mmol; see WO 01/28992) was
dissolved in DCM (30 mL). Trifluoroacetic acid (22.2 g, 194.7 mmol) was
added and the solution was stirred for 2 h. The mixture was concentrated
under reduced pressure, redissolved in toluene and acetonitrile and
concentrated in vacuo again. The product mixture was dissolved in
acetonitrile (50 mL) and solid K2CO3 (9.7 g, 10.2 mmol) was
added. The mixture was filtered and concentrated under reduced pressure.
The mixture was then redissolved in a mixture of EtOAc and a saturated
solution of NaHCO3. The mixture was extracted twice with DCM, the
combined organic extracts dried (Na2SO4) and evaporated to
afford 1.6 g (68.7%) of the title compound.

[0432]4-[3-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propoxy]benzonitrile
(6.5 g, 0.0226 mol; see WO 01/28992) and tert-butyl 2-bromoethylcarbamate
(6 g, 0.0271 mol; see WO 01/28992) were dissolved in 80 mL of dry
acetonitrile. Anhydrous potassium carbonate (4.68 g, 0.034 mol) was added
and the mixture was stirred at 60° C. overnight. A further portion
of tert-butyl 2-bromoethylcarbamate (2.53 g, 0.0113 mol) was added and
the reaction heated at 65° C. overnight. The reaction mixture was
then filtered and the filtrate concentrated under reduced pressure. The
product was purified by column chromatography using methanol-chloroform
as eluent to give the sub-title compound (4.5 g) as a yellow solid.

[0433](2-{7-[3-(4-Cyanophenoxy)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3--
yl}-ethyl)carbamic acid tert-butyl ester (4.5 g, 0.0104 mol; see step (i)
above) was added to a solution of HCl in dioxane. The reaction was
stirred at room temperature for 2 h, after which the reaction mixture was
filtered and the resultant solid washed with dioxane, then diethyl ether
and dried to give the title compound (3.89 g) as a white solid.

[0434]To a cooled solution of triphosgene (76 g, 0.256 mol, 0.75 eq.) in
dry DCM (150 mL) was added, dropwise at 0° C. over a period of 3
hrs under a N2 atmosphere, a mixture of tert-butylamine (25 g,
0.3418 mol, 1.0 eq.), DMAP (2.08 g, 0.017 mol, 0.05 eq.) and
triethylamine (67.1 g, 0.6836 mol, 2.0 eq.) in dry DCM (100 mL). After
addition of the mixture was complete, the reaction mixture was stirred at
RT for 12 hrs. The reaction mixture was cooled to 0° C. and
2-bromoethanol (106.8 g, 0.854 mol, 2.5 eq.) was added. The reaction
mixture was then stirred at RT for 6 hrs, before being diluted with water
and extracted with DCM. The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, and then concentrated under
reduced pressure. The resulting residue was distilled under reduced
pressure to yield carbamate the sub-title compound as a colourless
liquid. Yield: 28 g.

[0436]{2-[7-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}tert-butyl--
carbamate (5 g; see step (ii) above) was dissolved in dry dioxane (50 mL)
and the resulting solution cooled to 0° C. To this solution was
added, dropwise with continuous stirring, 100 mL of dry dioxane saturated
with HCl. The reaction mixture was stirred at RT for 1 hr. Dioxane was
decanted carefully and the hygroscopic solid precipitate was washed with
dry ether twice and then dried under vacuum to yield the dihydrochloride
salt as a white solid. This salt was dissolved in dry methanol (100 mL),
to which was then added 10% palladium on carbon. The resulting mixture
was stirred under a H2 atmosphere for 12 hrs. The reaction mixture
was filtered through Celite®, the filtrate concentrated under reduced
pressure and the resulting solid dried under high vacuum to provide the
title compound as a pale yellow solid. Yield: 3.8 g.

[0437]NaBH3CN (19.3 g, 0.3061 mol) was added in 3 portions to a
cooled (15° C.) solution of 5-bromoindole (20 g, 0.10 mol) in
glacial acetic acid (500 mL) and stirred for 2 h at this same
temperature. The reaction mixture was quenched with water, cooled and
basified with a sodium hydroxide pellet. It was then extracted with
diethyl ether. The organic layer was washed with water and brine, dried
over sodium sulfate, concentrated and purified by column chromatography
over silica gel to give the sub-title compound as a pale yellow solid.
Yield: 20 g.

(ii) 5-Bromo-1-(trifluoroacetyl)indoline

[0438]5-Bromo-2,3-dihydro-1H-indole (20 g, 0.1010 mol; see step (i) above)
was taken in (100 mL) of DCM and cooled to 0° C. Trifluoroacetic
anhydride (42.42 g, 0.2020 mol) was added dropwise to the reaction
mixture, which was then stirred for 30 min. The reaction mixture was
quenched with water and extracted with ethyl acetate. The organic layer
was washed with water and brine, dried over sodium sulfate, concentrated
and purified by column chromatography over silica gel to give the
sub-title compound as a white solid. Yield: 28 g.

(iii) 1-(2,2,2-Trifluoroacetyl)-2,3-dihydro-1H-indole-5-carbonitrile

[0439]1-(5-Bromo-2,3-dihydro-1H-indol-1-yl)-2,2,2-trifluoroethanone (19 g,
0.0646 mol; see step (ii) above) was dissolved in DMF (50 mL). CuCN (8.68
g, 0.0969 mol) was then added and the reaction mixture was stirred at
160° C. for 4 days, before being cooled to RT, diluted with water
and extracted with ethyl acetate. The organic layer was washed with water
and brine, dried over sodium sulfate then concentrated under reduced
pressure. The resulting residue was purified by column chromatography to
give the sub-title compound as a white solid. Yield: 13 g.

(iv) 2,3-Dihydro-1H-indole-5-carbonitrile

[0440]1-(2,2,2-Trifluoroacetyl)-2,3-dihydro-1H-indole-5-carbonitrile (13
g, 0.0542 mol; see step (iii) above) was dissolved in THF (100 mL), to
which 1% NaOH was then added. After stirring for 5 h at RT, the reaction
mixture was extracted with ethyl acetate. The organic layer was washed
with water and brine, dried over sodium sulfate and solvent was
evaporated to provide the sub-title compound as a pale yellow solid.
Yield: 8 g.

(v) 1-(3-Chloropropionyl)-2,3-dihydro-1H-indole-5-carbonitrile

[0441]To a solution of 2,3-dihydro-1H-indole-5-carbonitrile (8 g, 0.0556
mol; see step (iv) above) in DCM (50 mL) at 0° C. was added
N,N-dimethylaniline (13.5 g, 0.1112 mol) followed by 2-chloropropionyl
chloride (8.46 g, 0.0667 mol). The reaction mixture was stirred for 3 h
before being diluted with water and extracted with DCM. The organic layer
was washed with water and brine, dried over sodium sulfate and then
concentrated under reduced pressure. The resulting residue was purified
by column chromatography over silica gel to yield the sub-title compound
as a pale yellow solid. Yield: 10.5 g.

[0443]tert-Butyl
7-[3-oxo-3-(5-cyano-2,3-dihydro-1H-indol-1-yl)propyl]-9-oxa-3,7-diazabicy-
clo[3.3.1]nonane-3-carboxylate (5 g, 0.017 mol; see step (vi) above) was
taken up in 50 mL of dioxane that was saturated with HCl gas. The mixture
was then stirred for 1 h under nitrogen atmosphere at RT. The resulting
solid was filtered and washed with ether and then dried under vacuum to
yield 4.42 g of the title compound as an off white solid.

Preparation E

4-Cyano-N-[2-(9-oxa-3,7-diazabicyclo[3.3.1non-3-yl)ethyl]benzene-sulfonami-
de

(i) N-(2-Bromoethyl)-4-cyanobenzenesulfonamide

[0444]To an ice cooled solution of 2-bromoethylamine hydrogenbromide (12.2
g, 0.0595 mol) in dry dichloromethane (100 mL) was added triethylamine
and the mixture stirred for 15 min. 4-Cyanobenzenesulfonyl chloride (10
g, 0.0486 mol) in dichloromethane was added, dropwise. Stirring was
continued at RT for 1 h. The reaction mixture was diluted with
dichloromethane, washed with water, followed by brine, then dried over
sodium sulfate. Solvents were evaporated and the residue crystallized
from petroleum ether to give 12.5 g of the sub-title compound as a pale
yellow solid.

[0446]7-[2-(4-Cyanobenzenesulfonylamino)ethyl]-9-oxa-3,7-diaza-bicyclo[3.3-
.1]-nonane-3-carboxylic acid tert-butyl ester (5 g; see step (ii) above)
was taken up in 30 mL of dioxane that was saturated with HCl gas. The
mixture was stirred for 1 h before the dioxane was decanted off and the
remaining solid was washed with diethyl ether, yielding the HCl salt of
the title compound. This salt was then taken up in DCM-NaHCO3 (200
mL, 1:1) and the resulting mixture stirred for 1 h at RT. The compound
was extracted with dichloromethane, washed with water, brine and dried
over sodium sulfate. Solvent evaporation under reduced pressure yielded
3.4 g of the title compound as white solid.

[0448]Hydrochloric acid (140 mmol, 35 mL of a 4 M solution in dioxane) was
added to an ice-cooled slurry of the diacetate salt of
(2-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}eth-
yl)carbamic acid tert-butyl ester (10.75 g, 20 mmol; see step (i) above)
in dioxane (50 mL). The reaction mixture was stirred at RT overnight.
Another 65 mL (260 mmol) of 4 M HCl solution was added, after which the
reaction mixture was stirred for three hours and then evaporated. The
residue was dissolved in water and washed with diethyl ether.
Freeze-drying of the aqueous phase gave 8.3 g (97%) the title compound as
a white solid.

[0451]3,4-Dihydroxybenzaldehyde (20 g, 0.144 mol) and potassium carbonate
(40 g, 0.2898 mol) were taken up in dry DMF (1 L) and cooled to
-78° C. A Dewar condenser was fitted and freon gas (CHClF2)
was passed through the reaction mixture for 1 h. The reaction mixture was
stirred at 85° C. overnight. Solvent was evaporated under reduced
pressure and the residue purified by column chromatography over silica
gel (using petroleum ether in ethyl acetate as eluent) to yield the
sub-title compound as a pale yellow liquid. Yield: 11 g.

(ii) Methyl triphenylphosphonium iodide

[0452]To a solution of triphenylphosphine (30 g, 0.114 mol) in benzene
(200 mL) was added methyl iodide (11 ml, 0.1756 mol) dropwise, and the
solution stirred at room temperature for 15 min under a nitrogen
atmosphere. The sub-title compound formed as a colourless solid, which
was filtered and then dried. Yield: 30 g.

(iii) 1,2-Bis(difluoromethoxy)-4-vinylbenzene

[0453]Potassium tert-butoxide (6.7 g, 0.0683 mol) was taken in dry THF (25
mL) and stirred at 0° C. under a nitrogen atmosphere for 15 min.
Methyl triphenylphosphonium iodide (27.6 g, 0.0683 mol; see step (ii)
above) was then added, followed by 3,4-bis(difluoromethoxy)benzaldehyde
(8 g, 0.034 mol; see step (i) above). The reaction mixture was then
stirred for 1 h at RT, before being quenched with water. The organic
solvents were evaporated under reduced pressure and the aqueous layer
extracted with dichloromethane. Evaporation of the solvents followed, by
chromatography of the residue over silica gel (using petroleum ether in
ethyl acetate as eluent) afforded the sub-title compound as a pale yellow
liquid. Yield: 6.5 g

(iv) 2-[3,4-Bis(difluoromethoxy)phenyl]ethanol

[0454]To a solution of 1,2-bis(difluoromethoxy)-4-vinylbenzene (10 g,
0.0431 mol; see step (iii) above) in 25 mL of THF was added, dropwise,
borane-methyl sulfide complex (10 mmol; 10 mL of a 1 M solution in THF).
The resulting mixture was stirred at 60° C. for 1 h, before being
cooled to RT. Excess borane was decomposed by adding few drops of water
and the resultant mixture refluxed for 1 h with 2 M NaOH (100 mL) 50%
H2O2 (87 mL). The mixture was then extracted with
dichloromethane, washed with water and then brine, and dried over sodium
sulfate. Solvent evaporation under reduced pressure gave the sub-title
compound as a pale yellow liquid. Yield: 6 g.

(v) 4-(2-Bromoethyl)-1,2-bis(difluoromethoxy)benzene

[0455]2-[3,4-Bis(difluoromethoxy)phenyl]ethanol (6 g, 0.024 mol; see step
(iv) above) and triphenylphosphine (12.6 g, 0.048 mol) were taken up in
dichloromethane (100 mL) and cooled to 0° C. CBr4 (15.9 g,
0.048 mol) in dichloromethane was added dropwise, and the mixture stirred
at RT overnight under a nitrogen atmosphere. The reaction mixture was
filtered, the filtrate concentrated under reduced pressure and the
residue purified by column chromatography over silica gel (using 20%
ethyl acetate in petroleum ether as eluent) to give the title compound as
a yellow liquid. Yield 5.2 g.

[0459]4-Cyanobenzenesulfonyl chloride (6 g, 0.0297 mol) in 50 ml of dry
DCM was added at 0° C. to a solution of N-methylethanolamine (2.67
g, 0.0356 mol) and triethylamine (7.49 g, 0.0742 mol) in dry
dichloromethane (75 ml) under nitrogen atmosphere and stirred at RT for 2
h. The reaction mixture was quenched with water and extracted with
dichloromethane. Organic layer was washed with water and brine and dried
over sodium sulfate. Solvent evaporation under reduced pressure afforded
crude product as solid. This solid was then washed with petroleum ether
(three times) and dried under vacuum to give the sub-title compound (5.18
g) as white solid.

[0461]4-Cyano-N-methyl-N-(2-oxo-ethyl)-benzenesulfonamide (5.17 g, 0.0215
mol; see step (i) above) in dry DCM (30 ml) was added at RT and stirring
continued at RT for 2 h. The reaction mixture was quenched with
triethylamine (10.85 g) at -78° C. and slowly warmed to RT. 10%
Citric acid was added and the compound was extracted with dichloro
methane. The combined organic layer was washed with water and brine and
dried over sodium sulfate. Solvent evaporated under reduced pressure to
give the sub-title compound (4.97 g) as yellow oil. This was taken for
next step with out further purification.

[0462]A mixture of step (ii) product
4-Cyano-N-methyl-N-(2-oxo-ethyl)-benzenesulfonamide (4.97 g), and
9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester
(4.95 g; see WO 01/28992) and acetic acid (1.7 ml) in dry dichloromethane
(50 ml) was stirred at RT for 3 h and then cooled to 0° C.
NaBH3CN (1.96 g, 0.0312 mol) was added and stirring continued at RT
overnight under nitrogen atmosphere. The reaction mixture was quenched
with water, extracted with dichloromethane, washed with water and brine
and dried over sodium sulfate. Solvent evaporated under reduced pressure
and the residue was purified by column chromatography over silica gel
using 28% ethyl acetate in petroleum ether eluent to give the sub-title
compound (2.2 g) as a liquid.

[0466]The sub-title compound was made in analogy with preparation J (i)
above using
4-[3-(9-Oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-propoxy]-benzonitrile in
place of 4-[2-(9-Oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethoxy]-benzonitri-
le (see WO 01/28992).

[0467](3-{7-[3-(4-Cyano-phenoxy)-propyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]non-
-3-yl}-propyl)-carbamic acid tert-butyl ester (3.5 g) from step (i) above
was taken in 25 ml of dioxane (saturated with HCl gas) and stirred at
room temperature for 30 min under nitrogen atmosphere. Dioxane was
decanted, the solid was washed with diethyl ether (3 times) and dried
under vacuum to yield (2.8 g) of the title compound as white powder.

[0468]4-Cyanobenzenesulfonyl chloride (5 g, 0.0248 mol) was added dropwise
to a solution of 3-bromopropylamine hydrobromide (6.61 g, 0.0302 mol) and
triethylamine (6.26 g, 0.062 mol) in dry dichloromethane (50 ml) at
0° C. and stirred at room temperature overnight under nitrogen
atmosphere. The reaction was quenched with water and extracted with
dichloromethane. The organic layer was washed with water, brine and dried
over sodium sulfate.

[0469]Solvent evaporation under reduced pressure afforded the sub-title
compound (6.39 g) as a solid. This was used in the next step without
further purification

[0471]7-[3-(4-Cyano-benzenesulfonylamino)-propyl]-9-oxa-3,7-diaza-bicyclo[-
3.3.1]nonane-3-carboxylic acid tert-butyl ester (4.29 g, see step (ii)
above) was taken in 20 ml of dioxane, 40 ml of diethylether (saturated
with HCl gas) was added and stirred for 1 h at RT under nitrogen
atmosphere. Solvent was decanted. The solid was washed with dry
diethylether (4 times) and dried under vacuum to give the title compound
(5.3 g) as a white solid.

[0473]7-(4-Cyanobenzyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic
acid tert-butyl ester from step (i) above (10 g) was taken in 15 ml of
dioxane (saturated with HCl gas) and stirred for 1 h at RT under nitrogen
atmosphere. Dioxane was decanted, the precipitated solid was filtered,
washed with dry diethyl ether (4 times) and dried under vacuum to give
HC1 salt of the sub-title compound (7.5 g) as a powder. This was directly
taken for next step without further purification.

[0475]{3-[7-(4-Cyano-benzyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-propy-
l}-carbamic acid tert-butyl ester (7 g from step (iii) above) was taken in
50 ml of dioxane (saturated with HCl gas) and stirred for 1 h at RT under
nitrogen atmosphere. Dioxane was decanted, the precipitated solid was
filtered and washed with dry diethylether (4 times) and dried under
vacuum to give the title compound (6.5 g) as a powder.

[0476]Bromine (68.7 ml, 1.339 mol) dissolved in acetic acid (300 ml) was
added drop by drop to a cooled solution of 2-fluorophenol (150 g, 1.339
mol) in acetic acid (1300 ml) and the reaction mixture was stirred at
room temperature overnight. The reaction mixture was quenched with aq.
sodium bisulfite solution and extracted with dichloromethane. The organic
layer was washed with water and brine and dried over sodium sulfate.
Solvent evaporation under reduced pressure afforded
4-bromo-2-fluorophenol (210 g) as a liquid. This was directly taken for
next step without further purification.

(ii) 4-Bromo-2-fluoro-1-methoxybenzene

[0477]Methyl iodide (182.1 ml, 1.319 mol) was added at 0° C. to a
well stirred suspension of 4-bromo-2-fluorophenol (210 g, 1.099 mol, from
step (i) above ) and K2CO3 (303.92 g, 2.19 mol) in dry acetone
(1.7 L) and stirring continued at 60° C. for two days under
nitrogen atmosphere. The reaction mixture was filtered and the solvent
was concentrated under reduced pressure to yield 4-bromo-2-fluoro-anisole
(225 g) as a liquid. This was directly taken for next step without
further purification.

(iii) 3-Fluoro-4-methoxybenzonitrile

[0478]A mixture of 4-Bromo-2-fluoro-1-methoxybenzene (107 g, 0.5244 mol,
from step (ii) above), CuCN (70.4 g, 0.7866 mol) in dry DMF (150 ml) was
stirred at 120° C. overnight. The reaction mixture was cooled to
room temperature, diluted with water and extracted with ethyl acetate.
Organic layer was washed with water and brine and dried over sodium
sulfate. Solvent evaporation under reduced pressure followed by column
chromatography over silica gel using 3% ethyl acetate in petroleum ether
gave the sub-title compound (24.4 g) as a solid.

(iv) 3-Fluoro-4-hydroxy-benzonitrile

[0479]BBr3 (23 ml, 0.242 mol) was added to
3-Fluoro-4-methoxy-benzonitrile (24.4 g, 0.16 mol) in dichloromethane
(200 ml) at -78° C. and stirring continued overnight at room
temperature. Another portion of BBr3 (23 ml, 0.242 mol) was added at
-78° C. and stirring continued at RT for 2 days under nitrogen
atmosphere. The reaction mixture was quenched with ice water and
extracted with dichloromethane. Organic layer was washed with water and
brine, and dried over sodium sulfate. Solvent evaporation under reduced
pressure gave 20 g of the sub-title compound as a solid. This was taken
for next step without further purification.

[0481]A suspension of 4-(2-Bromo-ethoxy)-3-fluoro-benzonitrile (21.6 g,
0.0885 mol, from step (v) above),
9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester
(21.1 g, 0.07965 mol; see WO 01/28992) and dry K2CO3 (48.9 g,
0.354 mol) in 200 ml of dry acetonitrile was stirred at 60° C. for
five days under N2 atmosphere. The reaction mixture was filtered
through celite and filtrate was concentrated under reduced pressure. The
residue was purified by column chromatography over silica gel using 27%
ethyl acetate in petroleum ether, as eluent to yield the sub-title
compound (20.5 g) as a solid.

[0482]7-[2-(4-Cyano-2-fluoro-phenoxy)-ethyl]-9-oxa-3,7-diaza-bicyclo[3.3.1-
]nonane-3-carboxylic acid tert-butyl ester (20.5 g, from step (vi) above)
was taken in 20 ml of dioxane and added 100 ml of dioxane (saturated with
HCl gas) and stirred for 1 h at RT under nitrogen atmosphere. Solvent was
decanted and the precipitated solid was washed with dry diethylether (4
times) and dried under vacuum to give HCl salt of the sub-title compound
(21 g) as a solid.

[0484](2-{7-[2-(4-Cyano-2-fluoro-phenoxy)-ethyl]-9-oxa-3,7-diaza-bicyclo[3-
.3.1]non-3-yl}-ethyl)-carbamic acid tert-butyl ester (4.6 g from step
(viii) above) was taken in dry dichloromethane (20 ml) and cooled to
0° C. Trifluoro acetic acid (75 ml) was added drop by drop and the
reaction mixture was stirred at RT for 2 h under nitrogen atmosphere.
Solvent and trifluoroacetic acid were evaporated under reduced pressure
to give the TFA salt of the sub-title compound (7.6 g) as an oil.

[0485]4-{2-[7-(2-Amino-ethyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-etho-
xy}-3-fluoro-benzonitrile trifluoroacetic acid salt (8.3 g, 12.3 mmol,
from step (viv) above) was dissolved in dioxane (15 ml). HCl (15 ml of a
4M solution in dioxane) was added whilst stirring resulting in the
precipitation of the HCl-salt. The salt was filtered and dried, dissolved
in water and freeze dried. Yield: 3.6 g of the title compound as a solid.

[0488](3-{7-[2-(4-Cyano-2-fluoro-phenoxy)-ethyl]-9-oxa-3,7-diaza-bicyclo[3-
.3.1]non-3-yl}-propyl)-carbamic acid isopropyl ester (5.8 g, from step
(ii) above) was taken in dry dichloromethane (25 ml) and cooled to
0° C. Trifluoroacetic acid (75 ml) was added drop by drop and the
reaction mixture was stirred at RT for 2 h under nitrogen atmosphere.
Solvent and trifluoroacetic acid were evaporated under reduced pressure
to give the TFA salt of the sub-title compound (9 g) as an oil.

[0489]4-{2-[7-(3-Amino-propyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-eth-
oxy}-3-fluoro-benzonitrile TFA-salt (7.79 g, 11.3 mmol, from step (iii)
above) was dissolved in dioxane (15 ml). HCl (14 ml of a 4M solution in
dioxane was added. The HCl-salt precipitated, the dioxane was decanted
off and to the solid was added dioxane (10 ml ) followed by HCl (4 ml in
dioxane). The solvent was decanted off and the solid was dried under
vacuum. The solid was dissolved in water (5 ml) and freeze dried giving
2.98 g of the title compound

[0490]Chloroethane sulfonyl chloride (4.8 g, 0.029 mol) was added drop by
drop to solution of 4-aminomethyl benzonitrile methan sulphonic acid salt
acid (7 g, 0.029 mol) and pyridine (24 ml) in dry dichloromethane (25 ml)
at -5° C. under nitrogen atmosphere. The reaction mixture was
stirred at RT for 2 days and then partitioned between water and
dichloromethane. The organic layer was washed with water and brine and
dried over sodium sulfate. Solvent was evaporated under reduced pressure
and the residue was purified by column chromatography over silica gel
using 1% methanol in chloroform as eluent to give mixture of the
sub-title compound and ethenesulfonic acid 4-cyano-benzylamide (3.4 g) as
a solid. This was directly taken for next step without further
purification.

[0492]7-[2-(4-Cyano-benzylsulfamoyl)-ethyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]-
nonane-3-carboxylic acid tert-butyl ester (2.2 g, from step (ii) above)
was taken in dry dioxane (5 ml) and was added 15 ml of dioxane (saturated
with HC1 gas) and stirred at RT for 30 min. The precipitated solid was
filtered, washed with dry diethylether (three times) and finally dried
under vacuum to give the title compound (1.96 g) as a solid.

Preparation Q

4-(2-Bromoethyl)-1,2-difluorobenzene

(i) 1,2-Difluoro-4-(2-methoxy-vinyl)-benzene

[0493]Potassium tert butoxide (11 g, 0.098 mol) was added to methoxymethyl
triphenyl phosphonium chloride (31.12 g, 0.091 mol) in 150 ml of dry THF
at -30° C. under argon atmosphere and stirred for 1 h.
3,4-difluorobenzaldehyde (10 g, 0.07 mol) in 60 ml of THF was added
dropwise at the same temperature and stirring continued for 3 h at room
temperature. The reaction mixture was treated with 100 ml water, 150 ml
petroleum ether and filtered through celite. Organic layer was separated
and aq. layer was extracted with petroleum ether (2×100 ml).
Combined organic layer was washed with brine and dried over sodium
sulfate. Solvent evaporation under reduced pressure followed by
purification over silica gel using petroleum ether as eluent afforded
(5.5 g) of the sub-titles compound as a colorless liquid.

(ii) (3,4-Difluoro-phenyl)-acetaldehyde

[0494]To a solution of 1,2-difluoro-4-(2-methoxy-vinyl)-benzene (5.5 g,
0.032 mol, from step (i) above) in 80 ml acetone was added 66 ml of 3 (M)
HCl and stirred at 45° C. for 4 h. Acetone was evaporated under
reduced pressure and the residue was

partitioned between water and ether. The organic layer was washed with
NaHCO3, brine and dried over sodium sulfate. Solvent evaporation
under reduced pressure afforded (5.5 g) of the sub-title compound as a
liquid. This was directly taken for next step without further
purification.

(iii) 2-(3,4-Difluoro-phenyl)-ethanol

[0495]NaBH4 (1.46 g, 0.038 mol) was added at 0° C. to a
solution (3,4-difluoro-phenyl)-acetaldehyde (5.5 g 0.35 mol, from step
(ii) above) in 90 ml ethanol and stirred at RT overnight. The solvent was
evaporated under reduced pressure and the residue was partitioned between
50 ml of 1 N HCl and 50 ml of diethylether. Organic layer was washed with
water, dried over sodium sulfate and solvent evaporated under reduced
pressure to give (5.5 g) of the sub-title compound as a liquid. This was
directly taken for next step without further purification.

(iv) 4-(2-Bromo-ethyl)-1,2-difluorobenzene

[0496]A mixture of 2-(3,4-difluoro-phenyl)-ethanol (5 g, 0.032 mol, from
step (iii) above), 51.84 ml (49%, 0.64 mol) of HBr in acetic acid and 5
ml of sulfuric acid was stirred at 100° C. for 4 h. The reaction
mixture was poured into ice and extracted with diethylether. Organic
layer was washed with NaHCO3, water and dried over sodium sulfate.
Solvent evaporation under reduced pressure followed by purification
(three times) over silica gel using petroleum ether as eluent afforded
(1.8 g) of the title compound as a liquid.

Preparation R

4-Bromomethyl-3-fluoro-benzonitrile

(i) (4-Bromo-2-fluoro-phenyl)-methanol

[0497]To a solution of 4-bromo-2-fluorobenzaldehyde (25 g, 0.123 mol) in
methanol (250 ml) was added NaBH4 (7.02 g, 0.1847 mol) and the
reaction mixture was stirred at RT for 2 h. The reaction mixture was
diluted with 25 ml of water and solvent evaporated under reduced
pressure. The compound was extracted with ethyl acetate, organic layer
was washed with water and brine and dried over sodium sulfate. Solvent
evaporation under reduced pressure afforded the sub-title compound (25 g)
as an oil. This was directly taken for next step without further
purification.

[0499]Carbon tetrabromide (5.7 g, 0.172 mol) in dry dichloromethane (150
ml) as added to a solution of step 3-fluoro-4-hydroxymethylbenzonitrile
(13 g, 0.086 mol, from step (ii) above) and triphenyl phosphine (45 g,
0.172 mol) in dry dichloromethane (50 ml) and stirred at RT overnight
under nitrogen atmosphere. The reaction was quenched with water,
extracted with dichloromethane, washed with water and brine and dried
over sodium sulfate. Solvent evaporated under reduced pressure and the
residue was purified by column chromatography over silica gel using 10%
ethyl acetate in petroleum ether as eluent to give the title compound (8
g) as an off-white solid.

[0501]A mixture of 2,6-difluoro-4-cyanophenol (6 g, 0.038 mol),
1,3-dibromopropane (46.9 g, 0.23 mol) and dry potassium carbonate (8 g,
0.058 mol) in dry DMF (50 ml) was stirred at RT overnight under nitrogen
atmosphere. Solvent was removed under reduced pressure and the residue
was purified by column chromatography over silica gel using 4% ethyl
acetate in petroleum ether as eluent to yield (9.6 g) of the title
compound as a liquid.

Preparation U

4-(3-Bromo-propoxy)-3-fluorobenzonitrile

(i) 3-Fluoro-4-(3-hydroxy-propoxy)-benzonitrile

[0502]A mixture of 4-cyano-2-fluoro phenol (5 g, 0.0365 mol; from prep
N(iv) above), 3-bromopropanol (10.15 g, 0.073 mol) and potassium
carbonate (7.6 g, 0.054 mol) in dry acetone (50 ml) was stirred at
60° C. overnight under nitrogen atmosphere. The reaction mixture
was filtered and the solvent was concentrated under reduced pressure. The
residue was purified by column chromatography over silica gel using 5%
ethyl acetate in petroleum ether to yield (5.5 g) of the sub-title
compound as a solid.

(ii) 4-(3-Bromopropoxy)-3-fluorobenzonitrile

[0503]PBr3 (8.14 g, 0.03 mol) was added drop by drop at 0° C.
to a solution of 3-fluoro-4-(3-hydroxypropoxy)-benzonitrile (5.5 g, 0.028
mol, from step (i) above in carbon tetrachloride (50 ml) and stirred at
room temperature overnight under nitrogen atmosphere. The reaction was
quenched with water, and extracted with dichloromethane. Organic layer
was washed with water, brine, dried over sodium sulfate and solvent
evaporated under reduced pressure. The residue was purified by column
chromatography over silica gel using 6% ethyl acetate in petroleum ether
as eluent to yield (4.3 g) of the title compound as a liquid.

Preparation U

Methanesulfonic acid 2-(2,6-difluoro-phenyl)-ethyl ester

(i) methyl-2,6-difluoro phenyl acetate

[0504]H2SO4 (conc., 0.75 ml) was added to a solution of
(2,6-difluoro-phenyl)-acetic acid (14 g, 0.0814 mol) in dry methanol (160
ml) and stirred at room temperature overnight. Solvent evaporated under
reduced pressure and the residue was partitioned between water and
diethyl ether. Organic layer was washed water, brine and dried over
sodium sulfate. Solvent evaporation under reduced pressure yielded 16 g
of methyl-2,6-difluoro phenyl acetate as pale yellow liquid. This was
directly taken for next step without further purification.

(ii) 2-(2,6-Difluoro-phenyl)-ethanol

[0505]LAH (4.7 g, 0.129 mol) in dry diethylether (400 ml) was added at
0° C. to a stirred suspension of methyl-2,6-difluoro phenyl
acetate (16 g, 0.086 mol, from step (i) above in dry diethylether (80 ml)
and stirred at room temperature for 2 h under nitrogen atmosphere. The
reaction mixture was quenched with water, NaOH and filtered. The aq.
Layer was again acidified with 1.5 N HCl and extracted with diethylether.
Organic layer was washed with water, brine and dried over sodium sulfate.
Solvent evaporation under reduced pressure afforded (13.5 g) of
2-(2,6-difluoro-phenyl)ethanol as aliquid. This was directly taken for
next step without further purification.

(iii) Methanesulfonic acid 2-(2,6-difluoro-phenyl)-ethyl ester

[0506]Methanesulfonyl chloride (10.76 g, 0.094 mol) was added at 0°
C. to a solution of 2-(2,6-difluoro phenyl)ethanol (13.5 g, 0.085 mol,
from step (ii) above) and triethylamine (12.93 g, 0.128 mol) in dry
dichloromethane (135 ml) and stirred for 3 h under nitrogen atmosphere.
The reaction was quenched with water, extracted with dichloromethane,
dried over sodium sulfate and solvent evaporated under reduced pressure
to give (18 g) of the title compound as an oil.

Preparation V

1-(2-Bromoethyl)-4-trifluoromethylbenzene

(i) 1-(2-Methoxy-vinyl)-4-trifluoromethylbenzene

[0507]Potassium tert butoxide (13.46 g, 0.120 mol) was added to
methoxymethyl triphenyl phosphonium chloride (38.30 g, 0.112 mol) in 150
ml dry THF at -30° C. under argon atmosphere and stirred for 1 h.
4-trifluoromethylbenzaldehyde (15.0 g, 0.086 mol) in 60 ml THF was added
dropwise at the same temperature and stirring continued for 3 h at room
temperature. The reaction mixture was treated with 100 ml water, 150 ml
petroleum ether and filtered through celite. Organic layer was separated
and the aq. layer was extracted with petroleum ether (2×100 ml).
Combined organic layer was washed with brine and dried over sodium
sulfate. Solvent evaporation under reduced pressure followed by
purification over silica gel using petroleum ether as eluent afforded
(10.5 g) of the sub-title compound as a colorless liquid. This was
directly taken for next step without further purification.

(ii) (4-Trifluoromethyl-phenyl)-acetaldehyde

[0508]To a solution of 1-(2-methoxy-vinyl)-4-trifluoromethylbenzene (10.5
g, 0.052 mol, from step (i) above) in 158 ml acetone was added 107.3 ml 3
M HCl and stirred at 45° C. for 4 h. Acetone was evaporated under
reduced pressure and the residue was partitioned between water and ether.
Organic layer was washed with NaHCO3, brine and dried over sodium
sulfate. Solvent evaporation under reduced pressure afforded the
sub-title compound (9.4 g ) as pale yellow liquid. This was directly
taken for next step without further purification.

(iii) 2-(4-Trifluoromethylphenyl)-ethanol

[0509]NaBH4 (2 g, 0.055 mol) was added at 0° C. to a solution
of 4-trifluoromethyl-phenyl)-acetaldehyde (9.4 g, 0.05 mol, from step
(ii) above) in 154 ml ethanol and stirred at RT overnight. The solvent
was evaporated under reduced pressure and the residue was partitioned
between 50 ml 1 N HCl and 50 ml diethyl ether. Organic layer was washed
with water, dried over sodium sulfate and the solvent evaporated under
reduced pressure to give 10 g of the sub-title compound as a liquid. This
was directly taken for next step without further purification.

(iv) 1-(2-Bromo-ethyl)-4-trifluoromethylbenzene

[0510]A mixture of step 2-(4-trifluoromethylphenyl)-ethanol (10 g, 0.053
mol, from step (iii) above), 86 ml (1.06 M) HBr in acetic acid and 10 ml
sulfuric acid was stirred at 100° C. for 4 h. The reaction mixture
was poured into ice and extracted with diethylether. The organic layer
was washed with NaHCO3, water and dried over sodium sulfate. Solvent
evaporation under reduced pressure followed by purification over silica
gel using petroleum ether as eluent afforded 5 g of the title compound as
a liquid.

[0511]A suspension of methoxymethyl triphenylphosphonium chloride (6.69 g,
19.5 mmol) in THF (200 mL) was cooled to ca. -20° C. n-BuLi (2.5 M
in hexanes, 7.2 mL, 18 mmol) was added in portions over 5 min and the
orange-red reaction mixture was stirred for an additional 15 min.
4-difluoromethoxybenzaldehyde (2.58 g, 15.0 mmol) in THF (50 mL) was
added at -10° C. and the reaction mixture was stirred at this
temperature for 30 min and then at room temperature for 19 h. Water (100
mL) was added and the mixture was concentrated under reduced pressure.
The remaining aqueous phase was extracted with ethyl acetate (2×100
mL) and the combined organic phase was washed with water (2×100 mL)
and brine (100 mL), dried over Na2SO4, and concentrated in
vacuo. The crude product was purified by three times repeated
chromatography on silica gel. (Horizon®, flash system from
Biotage®. Column: Flash 40+M, 40×150 mm. Eluent: 3% ethyl
acetate in heptane. Combination of pure fractions and concentration in
vacuo afforded 1.60 g (53%) of the title compound as a colourless oil.

[0513]To a solution of 1-difluoromethoxy-4-((E,Z)-2-methoxyvinyl)-benzene
(E/Z ratio ˜3:2,) (1.58 g, 7.9 mmol, from step (i) above ) in
acetone (20 mL) was added 3 M HCl (3.7 mL, 11.1 mmol) and the solution
was stirred at 45° C. for 4 h. After concentration under reduced
pressure, water (25 mL) was added to the residue and the aqueous phase
was extracted with diethylether (2×50 mL). The combined organic
phase was washed with saturated aqueous NaHCO3 (50 mL) and brine (50
mL), dried over Na2SO4, and concentrated in vacuo to give 1.32
g of crude product as a yellow oil with a purity of ca. 80%. The crude
product was used directly in the subsequent reduction step without
further purification.

[0516]A solution of 2-(4-difluoromethoxyphenyl)-ethanol (0.582 g, 3.09
mmol, from step (iii) above) in methylene chloride (8 mL) was cooled to
0° C. Triethylamine (0.52 mL, 3.7 mmol) was added followed by a
solution of methanesulfonyl chloride (0.26 mL, 3.4 mmol) in methylene
chloride (2 mL) and the reaction mixture was stirred at 0° C. for
90 min. The reaction mixture was diluted with methylene chloride (40 mL)
and the organic phase was washed with water (2×30 mL) and brine (30
mL), dried over Na2SO4, and concentrated in vacuo to give 0.78
g (95%) of the title compound as a colourless oil.

[0518]A mixture of 2-fluorophenol (2.24 g, 20.0 mmol), 1,3-dibromopropane
(20.3 mL, 200 mmol), and potassium carbonate (2.76 g, 20.0 mmol) in
acetonitril (30 mL) was heated at 80° C. overnight. The reaction
mixture was filtered and the filtrate was concentrated in vacuo to give
4.70 g of the title compound as a light yellow oil with a purity of ca.
80%. The product was used in the subsequent reaction step without further
purification.

[0520]A mixture of 2,5-difluorophenol (2.60 g, 20.0 mmol),
1,3-dibromopropane (20.3 mL, 200 mmol), and potassium carbonate (2.76 g,
20.0 mmol) in acetonitril (30 mL) was heated at 80° C. overnight.
The reaction mixture was filtered and the filtrate was concentrated in
vacuo to give 4.82 g of the title compound as a light yellow oil with a
purity of ca. 80%. The product was used in the subsequent reaction step
without further purification.

[0524]A mixture of 3-fluorophenol (2.24 g, 20.0 mmol), 1,3-dibromopropane
(20.3 mL, 200 nmol), and potassium carbonate (2.76 g, 20.0 mmol) in
acetonitril (30 mL) was heated at 80° C. overnight. The reaction
mixture was filtered and the filtrate was concentrated in vacuo. The
crude product was purified by chromatography on silica gel. (Horizon®,
flash system from Biotage®. Column: Flash 40+M, 40×150 mm.
Eluent: 3% ethyl acetate in heptane, Concentration in vacuo afforded 3.68
g of the title compound as a colourless oil with a purity of ca. 75%. The
product was used in the subsequent reaction step without further
purification.

[0526]To a suspension of sodium hydride (1.9 g of a 60% suspension in
mineral oil, washed with heptane) in THF (20 mL) was added ethylene
glycol (19.9 g, 0.32 mol) in portions over 15 min. The reaction mixture
was stirred at room temperature for 2 h and then heated to 80° C.
Benzylbromide (6.05 g, 32.0 mmol) in THF (30 mL) was added and the
reaction mixture was stirred at 80° C. for 3.5 h. After cooling to
room temperature, saturated aqeuous NH4Cl (75 mL) was added and the
phases were separated. The water phase was extracted with diethylether
(3×75 mL) and the combined organic phase was washed with saturated
aqueous NH4Cl (75 mL) and brine (75 mL), dried over MgSO4 and
concentrated in vacuo to afford 6.83 g (95%) of the sub-title compound as
an oil with a purity of ca. 90%.

[0528]A solution of 2-(4-fluorobenzyloxy)-ethanol (5.11 g, 30.0 mmol, from
step (i) above) in methylene chloride (60 mL) was cooled to -10°
C. Triethylamine (5.0 mL, 36 mmol) was added followed by methanesulfonyl
chloride (3.78 g, 33.0 mmol) and the reaction mixture was stirred at
-5° C. for 2 h. The reaction mixture was diluted with methylene
chloride (200 mL) and the organic phase was washed with water (2×75
mL) and brine (75 mL), dried over MgSO4, and concentrated in vacuo
to give 7.16 g (96%) of the title compound as a yellow oil.

[0530]Potassium carbonate (3.82 g, 27.6 mmol) was added to a mixture of
tert-butyl [2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamate
(5.00 g, 18.4 mmol) and 4-(bromomethyl)benzonitrile (3.61 g, 18.4 mmol)
in acetonitrile (150 mL). The mixture was heated to reflux over night,
cooled to room temperature, filtered and evaporated. The residue was
dissolved in dichloromethane (100 mL), washed with water and dried over
MgSO4. Purification by preparative HPLC gave 7.04 g (78%) of the
sub.title compound as a salt with one equivalent of acetic acid and one
equivalent of formic acid.

[0532]A saturated solution of HCl in ethyl acetate (200 mL) was added to
an ice-cooled slurry of the acetic and formic acid salt of tert-butyl
{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}carbama-
te (7.00 g, 14.2 mmol). The reaction mixture was stirred at room
temperature for 3 hours after which it was filtered and the resultant
solid was washed with ethyl acetate. Drying in vacuo gave 6.12 g (96%) of
the title compound with one equivalent of residual ethyl acetate.

[0534]To a solution of benzo[d]isoxazol-3-yl-acetic acid (0.86 g, 4.85
mmol) in anhydrous THF (40 mL) was added dropwise borane dimethylsulfide
complex (0.58 mL, 10 M, 5.8 mmol) at 0° C. The mixture was allowed
to warm to room temperature and was stirred over night. MeOH (10 mL) was
carefully added and when the gas evolution ceased, the mixture was heated
under gentle reflux for 4 hours. The reaction mixture was concentrated in
vacuo and the remainder was dissolved in dichloromethane (20 mL). An
aqueous solution of Na2CO3 (20 mL) was added and the aqueous
layer was extracted with dichloromethane (3×20 mL). The combined
organic layers were dried over Na2SO4 and concentrated in
vacuo. The crude product was purified by chromatography on silica gel
which afforded 537 mg (67.8%) of the title compound.

[0536]To a solution of 2-benzo[d]isoxazol-3-yl-ethanol (0.537 g, 3.29
mmol, from step (i) above ) and triethylamine (0.55 mL, 3.95 mmol) in
dichloromethane (20 mL) was added methanesulfonyl chloride (0.31 mL, 3.95
mmol) at 0° C. The reaction mixture was stirred for 1 hour and was
then extracted with water (2×20 mL) and brine (20 mL). The organic
layer was dried over Na2SO4 and concentrated in vacuo, which
afforded 818 mg (98%) of the title compound.

[0538]To a solution of 2-(2-fluorophenyl)-ethanol (4.00 g, 28.5 mmol) and
triethylamine (6.36 mL, 45.7 mmol) in dichloromethane (15 mL) was added
methanesulfonyl chloride (2.88 mL, 37.1 mmol) at -5° C. The
mixture was stirred for 4 hours and was allowed to slowly warm to room
temperature. The mixture was diluted with dichloromethane and extracted
with 1 M HCl and water. The organic layer was dried over Na2SO4
and concentrated in vacuo. The crude product was purified by column
chromatography, using dichloromethane as eluent, to afford 5.88 g (94.4%)
the title compound.

[0540]4-{(2S)-3-[7-(2-Aminoethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-2-
-hydroxypropoxy}benzonitrile (0.096 g, 0.28 mmol; see step Preparation A
above) was dissolved in a 1:2 ratio of DCM:acetonitrile (3 mL).
Triethylamine (0.17 g, 1.68 mmol) was added, followed by
phenylmethanesulfonyl chloride (0.068 g, 0.36 mmol). The mixture was
stirred at room temperature overnight with K2CO3 (0.38 g, 2.77
mmol) to ensure that the free base of triethylamine was in the reaction
mixture. The reaction mixture was filtered and the filtrate concentrated
under reduced pressure. Purification by preparative HPLC gave 0.1 g (72%)
of the title compound.

methanesulfonic acid 2-(4-difluoromethoxy-phenyl)-ethyl ester (0.128 g,
0.48 mmol, from Prep W above), potassium carbonate (0.210 g, 1.52 mmol),
and water (0.1 mL) in acetonitrile (4 mL) was heated by microwave
irradiation (160° C., 15 min). Solid material was filtered off and
the filtrate was loaded onto a cation-exchange column (SCX-2,
Isolute®, 2 g/15 mL). The column was washed with a solution of
methylene chloride/acetonitrile/methanol (2:1:1, 40 mL) and eluted with
20% methanol saturated with ammonia in methylene chloride (30 mL). The
filtrate was concentrated in vacuo and the crude product was purified by
chromatography on silica gel using methanol in chloroform as eluent.
Concentration in vacuo afforded 37 mg (18%) of the title compound as an
yellow oil.

[0555]A mixture of
4-cyano-N-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethyl]-benzenesulfo-
namide (0.101 g, 0.30 mmol) and 1-methyl-1H-indole-3-carbaldehyde (0.081
g, 0.51 mmol) in 1,2-dichloroethane (4 mL) was agitated for 1.5 hours at
room temperature. Sodium triacetoxyborohydride (0.216 g, 1.02 mmol) was
added and resulting mixture was agitated over night at room temperature.
An aqueous solution of Na2CO3 (3 mL) was added and the aqueous
layer was extracted with dichloromethane (3×4 mL). The combined
organic layers were concentrated in vacuo and the crude product was
purified by chromatography on silica gel using methanol saturated with
ammonia in dichloromethane as eluent, which afforded 76 mg (52.8%) of the
title compound.

[0557]4-{2-[7-(2-Amino-ethyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-etho-
xy}benzonitrile tri hydrochloride salt (1 g, 2.35 mmol; Prep F) and
3,5-dimethylisoxazole-4-sulfonyl chloride (0.597 g, 3 mmol) were
dissolved in DCM (25 mL). Triethylamine (1.95 mL, 3 mmol) was added and
the reaction mixture was stirred at room temperature overnight under a
nitrogen amosphere. The reaction mixture was concentrated and then
redissolved in DCM (25 mL) and transferred to a phase separator. The DCM
layer was washed with water (30 mL) and the layers were separated. The
retained water was extracted with DCM (25 mL) and the layers were
separated. The combined DCM fractions were concentrated under reduced
pressure. Purification was performed by precipitation from a mixture of
DCM, EtOAc and IPA to give a solid material (0.2 g, 17%).

[0560]N-(2-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-
-yl}ethyl)-3,5-dimethylisoxazole-4-sulfonamide (43 mg, 0.09 mmol, from
example 9 above ) and Cs2CO3 (86 mg, 0.26 mmol) were suspended
in acetouitrile (2 mL). Iodomethane (17 μl , 0.26 mmol) was added and
the reaction mixture was stirred at room temperature overnight under a
nitrogen amosphere. More iodomethane (17 μl, 0.26 mmol) was added. The
reaction mixture was left to stir for a further 20 h at room temperature
overnight under a nitrogen atmosphere. The reaction mixture was filtered
and the filtrate was concentrated under reduced pressure. The crude
product was purified by chromatography on silica gel using methanol
saturated with ammonia in dichloromethane as eluent, which afforded 39 mg
(88%) of the title compound.

[0562]4-{2-[7-(2-Amino-ethyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-etho-
xy}-3-fluoro-benzonitrile hydrochloride salt (0.266 g, 0.6 mmol; prep N
above) and 2,4-difluorobenzenesulfonyl chloride (0.170 g, 0.80 mmol) were
dissolved in DCM (6 mL). Triethylamine (0.416 mL, 3 mmol) was added and
the reaction mixture was stirred at room temperature for 20 h under a
nitrogen atmosphere. The reaction mixture was concentrated and then
redissolved in DCM (3 mL) and transferred to a phase separator. The DCM
layer was washed with water (3 mL) and the layers were separated. The
retained water was extracted with DCM (3 mL) and the layers were
separated. The combined DCM fractions were concentrated under reduced
pressure. The crude product was purified by chromatography on silica gel
using methanol saturated with ammonia in dichloromethane as eluent, which
afforded 173 mg (56%) of the title compound.

[0564]Cyanomethylenetri-n-butylphosphorane (90%, 0.158 g, 0.59 mmol) was
weighed into a microwave vial.
N-(2-{7-[2-(4-Cyano-2-fluoro-phenoxy)-ethyl]-9-oxa-3,7-diaza-bicyclo[3.3.-
1]non-3-yl}-ethyl)-2,4-difluoro-benzenesulfonamide (100 mg, 0.2 mmol, from
example 11 above) and THF (2 mL) were added. Methanol (16 μl, 0.39
mmol) was then added and the reaction was heated with microwave
irradiation at 160° C. for 15 min. MeOH (1 mL) was added and the
reaction was heated with microwave irradiation for a further 10 min in
order to consume excess reagent. The reaction mixture was concentrated
and the crude product was purified by chromatography on silica gel using
methanol saturated with ammonia in dichloromethane as eluent. The product
isolated could be purified further by recrystallisation from MeOH to give
a solid (55 mg, 53%).

[0709]Title compounds of the above Examples were tested in Test A above
and were found to exhibit D10 values of more than 5.5.

Example 15

[0710]Title compounds of the above Examples were tested in Test B above
and were found to exhibit pIC50 values of greater than 4.5. Indeed
the compounds of Examples 1 and 9 were found to have pIC50 values of
5.72 and 5.49, respectively.